IRIS and Mortality in Advanced HIV: Post-Pandemic Experience from a Single-Center Case Series

IRIS and Mortality in Advanced HIV: Post-Pandemic Experience from a Single-Center Case Series | 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 Case Report IRIS and Mortality in Advanced HIV: Post-Pandemic Experience from a Single-Center Case Series Emel Gurcuoglu, Bilge Tuna, Hatice Ortac, Vildan Gursoy This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7742557/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective: We aimed to retrospectively evaluate patients presenting with advanced human immunodeficiency virus (HIV) infection and AIDS-defining conditions following the pandemic, and to examine the occurrence of immune reconstitution inflammatory syndrome (IRIS) after antiretroviral therapy (ART) initiation. In addition, we sought to present our clinical experience. Materials and Methods: Between 2021 and 2025, we retrospectively reviewed 12 ART-naïve adults with advanced HIV infection and complete medical records. Demographic, immunological, and virological parameters, opportunistic infections, IRIS types, and treatment responses were recorded. Results: IRIS developed in all 11 patients (100%) who initiated ART. The median time to IRIS onset was 49 days (range: 20–213). Unmasking IRIS occurred in 63.6% of cases, while paradoxical IRIS accounted for 36.4%. Clinical manifestations included tuberculosis, cytomegalovirus infection, cryptococcosis, toxoplasmosis, Kaposi sarcoma, and lymphoma. Corticosteroid therapy was required in 63.6% of patients. Overall mortality was 33.3%, most frequently associated with cryptococcal meningitis, Pneumocystis jirovecii pneumonia, and Kaposi sarcoma. Conclusion: In our study, the high rates of IRIS and mortality observed among patients with advanced HIV infection and a substantial burden of AIDS-defining illnesses may represent an expected consequence of delayed presentation and increased antigen load. However, the single-center, retrospective design and the limited sample size restrict the generalizability of these findings. Therefore, prospective multicenter studies are needed to more clearly define early markers that may predict the development of IRIS. Clinical trial number: not applicable HIV advanced disease immune reconstitution inflammatory syndrome opportunistic infections mortality Figures Figure 1 Figure 2 Introduction The clinical course of HIV infection is determined by the interplay of several factors, including baseline immune reserve at diagnosis, the level of viral replication and antigenic burden, co-infections, and the timing of antiretroviral therapy (ART) initiation. While the introduction of ART has led to a marked reduction in opportunistic infections and AIDS-related malignancies, in some patients rapid immune recovery may trigger an exaggerated inflammatory response, thereby complicating the clinical course and contributing to increased morbidity and mortality ( 1 ). Patients presenting with profound immunosuppression and high antigenic burden are at particularly high risk for developing immune reconstitution inflammatory syndrome (IRIS), which substantially complicates clinical management ( 2 ). The COVID-19 pandemic further disrupted timely access to HIV diagnosis and treatment, resulting in a greater proportion of patients presenting at advanced stages of disease and making IRIS more clinically visible. In the post-pandemic period, the increased frequency of IRIS among ART-naïve individuals with advanced HIV, together with its expanding clinical spectrum and its strong association with mortality, has emerged as one of the most critical challenges in current clinical practice ( 3 ). This study presents the clinical experience of a tertiary care center with ART-naïve patients diagnosed with advanced HIV infection in the post-pandemic era. This 12-case series aims to describe the frequency and clinical subtypes of IRIS (unmasking and paradoxical), characterize its immunovirological dynamics, and assess its impact on survival, while also sharing insights into the clinical presentations and management strategies observed in late presenters. Materials and Methods This retrospective case series included adult patients who presented with advanced HIV infection (CD4 < 200 cells/mm³ and/or presence of an AIDS-defining condition) and were followed at our tertiary care center during the post-pandemic period (2021–2025). Eligibility criteria required available baseline data including CD4 count, CD4/CD8 ratio, and HIV RNA level at diagnosis. Cases with documented secondary infections or drug reactions were included. Exclusion criteria were: prior or ongoing ART exposure at presentation, incomplete follow-up records precluding IRIS evaluation, acute HIV infection without advanced disease criteria, and pediatric age (< 18 years). The following parameters were recorded: demographic data, date of HIV diagnosis and ART initiation, ART regimen, baseline CD4 count, CD4/CD8 ratio, HIV RNA level, and presence of opportunistic infections, AIDS-related malignancies, or autoimmune conditions. During follow-up, IRIS occurrence, subtype (unmasking or paradoxical), time to onset, CD4 count and HIV RNA level at IRIS, and use of systemic corticosteroids were documented. Additional data included co-infections (HBV, HCV, syphilis), EBV serology, most recent CD4/CD8 ratio, last available HIV RNA level, and survival status. The classification of opportunistic infections and AIDS-defining conditions, as well as IRIS evaluation, was based on the World Health Organization (WHO) clinical staging system and the Centers for Disease Control and Prevention (CDC) AIDS case definition ( 4 – 6 ). IRIS was defined as the clinical manifestation of a previously undiagnosed opportunistic infection (unmasking IRIS) or the unexpected worsening of a known infection (paradoxical IRIS) following ART initiation and immune recovery. Confirmation required evidence of virological response, with alternative explanations such as new infections, natural disease progression, or drug toxicity excluded. In cases without laboratory confirmation, diagnosis was established through multidisciplinary clinical consensus. Diagnostic confirmation for specific conditions required: clinical suspicion supported by chest CT findings and positive immunofluorescence for Pneumocystis jirovecii pneumonia (PCP) Figs. 2 a and 2 b).; culture, molecular methods, or histopathology for tuberculosis; cerebrospinal fluid molecular analysis for central nervous system toxoplasmosis; and blood and/or CSF culture positivity for cryptococcosis (Fig. 1 ). Malignancies and dermatological lesions required histopathological reports, while gastrointestinal infections required endoscopic findings supported by culture, molecular, and/or histopathology. Treatment responses were reclassified according to the 2023 European AIDS Clinical Society (EACS) guidelines ( 7 ). Virological response was categorized as full suppression (HIV RNA < 50 copies/mL), partial suppression (significant log reduction with persistent detectability), or failure (no suppression or viral rebound). Immunological response was defined as an increase of at least 50–100 cells/mm³ in CD4 count within the first year, as recommended by the guidelines. One patient who could not initiate ART due to early mortality and another with incomplete immunovirological data were excluded from IRIS subtype and CD4/HIV RNA dynamic analyses but remained included in survival and mortality evaluations. Statistical Analysis Normality of distribution for continuous variables was assessed using the Shapiro–Wilk test. Variables with normal distribution were expressed as mean ± standard deviation, and those without normal distribution as median (minimum–maximum). Categorical variables were expressed as n (%). Statistical analyses were performed using SPSS software (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.), with a type I error threshold of 5%. Results For descriptive analyses, median values were preferred for variables with wide biological dispersion (e.g., CD4 count, HIV RNA level) to more accurately reflect central tendency and minimize the impact of outliers. According to CDC and WHO classifications, the majority of patients were in CDC stage 3 / WHO stage 4 (AIDS stage) at diagnosis, while only 1–2 patients had CD4 counts between 200–286/mm³, corresponding to CDC stage 2 / WHO stage 3 ( 8 ). The mean age was 42.2 ± 13.8 years, with a median of 45.5 (range: 21–61). Ten patients (83.3%) were male and two (16.7%) female. The mean time from diagnosis to ART initiation was 12.2 ± 28.3 days, with a median of 0 (0–88). One patient had remained untreated from diagnosis in 2017 until 2023, and another with cryptococcal sepsis and meningitis had died before ART initiation (Table 1 ). Table 1 Baseline clinical and laboratory characteristics of the study cohort (n = 12) Characteristic Value Age (years) 42.17 ± 13.81; median 45.5 (21–61) Sex Female: 2 (16.7%), Male: 10 (83.3%) Time from HIV diagnosis to ART initiation (days) * 12.20 ± 28.34; median 0 (0–88) IRIS Present: 11 (91.7%), Absent: 1 (8.3%) Time from ART to IRIS (days) 71.09 ± 59.57; median 49 (20–213) Type of IRIS ** Unmasking: 7/11 (63.6%), Paradoxical: 4/11 (36.4%) Systemic corticosteroid use Overall: 8/12 (66.7%); IRIS-related: 7/11 (63.6%) Baseline CD4 (cells/mm³) 99.79 ± 103.09; median 52.88 (9.09–286) Baseline CD4/CD8 ratio 0.16 ± 0.15; median 0.12 (0.02–0.53) Baseline HIV RNA (copies/mL) 5,675,183 ± 5,706,394.82; median 3,824,224 (90,813–14,491,703) CD4 at IRIS (cells/mm³) 310.10 ± 213.79; median 279.5 (40–635) HIV RNA at IRIS (copies/mL) 45,095.3 ± 128,481.75; median 2,883.5 (34–410,471) Last follow-up CD4 (cells/mm³) 382.18 ± 254.82; median 325.5 (73–910) Last follow-up CD4/CD8 ratio 0.54 ± 0.32; median 0.57 (0–1) Last follow-up HIV RNA Undetectable: 5/12 (41.7%); Detectable: median 190 (103–821) ART regimen No ART: 1 (8.3%); TDF/FTC/DTG: 7 (58.3%); BIC/FTC/TAF: 4 (33.3%) Co-infections Syphilis : 3 (25%); EBV positive: 8 (66.7%); HBV: 4 (33.3%); HCV: 1 (8.3%) Survival Death: 4 (33.3%), Alive: 8 (66.7%) * One patient with lymphoma was diagnosed with HIV in 2017 but remained untreated until 2023; this case was not included in the statistical calculations and is therefore not reflected in the “Time from HIV diagnosis to ART initiation” values. ** Percentages for IRIS subtypes are calculated based on the 11 patients who started ART and developed IRIS. IRIS developed in all 11 patients (100%) who received ART, while the patient who died prior to ART initiation was excluded from IRIS analyses. The mean time from ART initiation to IRIS onset was 71.1 ± 59.6 days, with a median of 49 (20–213). Unmasking IRIS was the predominant subtype (63.6%, n = 7), followed by paradoxical IRIS (36.4%, n = 4). IRIS subtypes and associated AIDS-defining illnesses were summarized in Table 2 . Table 2 AIDS-defining conditions and associated types of IRIS AIDS-defining condition Type of IRIS Cryptococcal infection + AIDS-RWS Death (ART not initiated) Disseminated herpes zoster + AIDS-RWS Unmasking(Unm) CMV colitis Oropharyngeal candidiasis + AIDS-RWS Unm. CMV retinitis Pneumocystis jirovecii pneumonia + AIDS-RWS Paradoxical (Par)P. jirovecii pneumonia Persistent lymphadenopathy + atypical pneumonia + AIDS-RWS Unm. lymphoma AIDS-RWS + vaginal candidiasis Unm. lymphoma CNS toxoplasmosis + AIDS-RWS Par.cutaneous IRIS + Unm Candida esophagitis Miliary tuberculosis + AIDS-RWS Par. tuberculosis Recurrent pneumonia + seborrheic dermatitis + AIDS-RWS Unm tuberculosis Disseminated herpes zoster + persistent lymphadenopathy + AIDS-RWS Par. HPV-related lesions Kaposi’s sarcoma + oropharyngeal candidiasis + AIDS-RWS Par. Kaposi’s sarcoma Oropharyngeal candidiasis + AIDS-RWS Unm. Kaposi’s sarcoma AIDS-RWS (AIDS-related wasting syndrome) is defined as ≥ 10% unintentional weight loss associated with ≥ 30 days of diarrhea or fever. Systemic corticosteroids were administered to 8 patients (66.7%); however, in one case steroids were used for cryptococcal meningitis prior to ART and were unrelated to IRIS. Thus, 7 of 11 patients (63.6%) received steroids for IRIS management. Steroid therapy was not required in cases of CMV colitis, CMV retinitis, paradoxical HPV, or unmasking tuberculosis. In patients treated with steroids, the median CD4 count increased from 84 cells/mm³ at diagnosis to 266 cells/mm³ during IRIS (mean 2.6-fold rise; range: 1.1–16.6), while median HIV RNA decreased from 3.6 × 10⁶ copies/mL to 7.9 × 10³ copies/mL, representing a mean decline of 2.7 log₁₀ (range: 0.95–3.73). Among the 7 patients receiving steroids for IRIS, three (42.9%) died and four survived. Patient-level changes in CD4 count, HIV RNA decline, and survival status were detailed in Table 3 . Table 3 Immunological and virological changes and survival among patients receiving corticosteroids Patients receiving steroids CD4 fold increase HIV RNA log₁₀ decline Survival Cryptococcal sepsis + meningitis* – – Death P. jirovecii pneumonia 1.08 3.67 Death CNS Lymphoma 2.38 0.95 Alive Lymphoma 7.67 2.94 Alive Seborrheic dermatitis + Candida esophagitis 1.77 1.55 Alive Miliary Tuberculosis 16.62 2.45 Alive Kaposi’s sarcoma* – – Death Kaposi’s sarcoma 2.76 3.73 Death * In the cryptococcal meningitis case, corticosteroids were administered before ART initiation and were therefore not related to IRIS. In one Kaposi’s sarcoma case, no laboratory confirmation was available during the suspected IRIS episode; the diagnosis was based on clinical and radiological findings At baseline, the mean CD4 count was 99.8 ± 103.1/mm³, with a median of 52.9 (9.1–286). The CD4/CD8 ratio averaged 0.16 ± 0.15 (median 0.12), reflecting profound immunodeficiency. The mean HIV RNA was 5,675,183 ± 5,706,395 copies/mL, with a median of 3,824,224 (90,813–14,491,703). During IRIS, the mean CD4 count rose to 310.1 ± 213.8/mm³ (median 279.5; 40–635), while median HIV RNA declined to 2,883 copies/mL (34–410,471). At the last follow-up, the mean CD4 count was 382.2 ± 254.8/mm³ (median 325.5; 73–910), and the CD4/CD8 ratio was 0.54 ± 0.32 (median 0.57). HIV RNA was undetectable in 41.7% of patients; among those with detectable viremia, the median level was 190 copies/mL (103–821). Overall, IRIS occurred in 11 of 12 patients (91.7%). The distribution of subtypes mirrored earlier findings, with unmasking IRIS accounting for 63.6% (n = 7) and paradoxical IRIS for 36.4% (n = 4). Corticosteroids were administered in 8 patients (66.7%), but only 7 cases were IRIS-related (63.6% of those starting ART). At the end of follow-up, overall survival was 66.7% (n = 8), while 33.3% (n = 4) died during the IRIS course. Baseline and follow-up clinical and laboratory features were summarized in Table 1 . According to the 2023 EACS criteria, treatment responses were heterogeneous. Complete virological suppression was achieved in five patients (Cases 2, 3, 5, 6, 10), while three (Cases 7, 8, 9) had partial responses (HIV RNA decline > 1–2 log₁₀ but remained detectable). Four patients (Cases 1, 4, 11, 12) experienced virological failure, with fatalities occurring particularly among those with PCP and KS. Immunologically, most patients met the EACS criterion of a + 50–100 cells/mm³ CD4 increase within the first year (e.g., Case 5: 267 to 910/mm³), though recovery was insufficient in some (Cases 4 and 11) and was associated with mortality. Among ART regimens, 7 patients (58.3%) received TDF/FTC/DTG, 4 (33.3%) BIC/FTC/TAF, and 1 remained untreated (8.3%). Among the 11 patients who initiated ART, virological and/or immunological response was achieved in 72.7% (n = 8), while 27.3% (n = 3) remained non-responders. EBV seropositivity was found in 66.7%, negative in 16.7%, and not tested in 16.7%. Co-infections included syphilis in 25% (n = 3), HBV in 33.3% (n = 4), and HCV in 8.3% (n = 1). During follow-up, four patients (33.3%) died and eight (66.7%) survived (Table 1 ). One patient died before ART could be initiated. Discussion This study describes the experience of a small cohort of ART-naïve patients with advanced HIV and offers additional insights into the biological and clinical spectrum of IRIS. Our findings suggest that delayed diagnosis and high antigen burden appeared to increase the risk of IRIS and AIDS-related mortality ( 9 – 11 ). Although international data suggest a decline in mortality, the 33.3% case-fatality rate in our cohort—comprising exclusively advanced cases—was higher than the 10–20% reported in previous studies ( 10 , 12 , 13 ). These results underscore the critical impact of late presentation and highlight the importance of strengthening early diagnostic programs and addressing stigma as essential components of HIV care. At baseline, a median CD4 count of 52.9/mm³, CD4/CD8 ratio of 0.12, and HIV RNA level of 3.8 × 10⁶ copies/mL reflected profound immunodeficiency, consistent with advanced-stage disease. During follow-up, a 5.3-fold increase in CD4 count and a 3.1 log decline in HIV RNA demonstrated the simultaneous occurrence of rapid immune reconstitution and viral suppression, in line with existing evidence on the pathogenesis of IRIS ( 1 ). In our series, unmasking IRIS was the most frequent presentation (63.6%), followed by paradoxical forms (36.4%), a distribution comparable to reports from other advanced cohorts ( 14 – 16 ). The relatively high proportion of unmasking IRIS likely reflected pandemic-related diagnostic delays and elevated antigen burden. The wide onset interval (20–213 days) emphasized that IRIS may arise throughout the treatment course and underscored the need for prolonged vigilance in advanced cases. No clear differences in outcomes were observed between patients receiving TDF/FTC/DTG and those on BIC/FTC/TAF. However, the lack of virological or immunological response in one-third of patients suggests that treatment success depended less on regimen choice than on baseline conditions—namely late diagnosis, high burden of opportunistic infections, and severe immunosuppression ( 2 , 13 , 17 , 18 ). Systemic corticosteroids were required in approximately two-thirds of cases. Nevertheless, patients with CMV colitis, CMV retinitis, paradoxical HPV, or unmasking tuberculosis did not require steroids, indicating that IRIS severity was shaped not only by immune recovery but also by antigen load, site of involvement, and host-specific immune responses (Table 3 ). Although steroid-treated patients showed a median 2.6-fold CD4 increase and 2.7 log₁₀ HIV RNA decline, survival in this group was only 57.1%, suggesting that corticosteroids alone were insufficient in advanced cases with high antigen burden. Larger, prospective studies are needed to clarify their impact on survival ( 19 ). Notable clinical observations further highlighted the heterogeneity of IRIS. One patient with unmasking EBV-associated lymphoma presented with hemostatic abnormalities, including elevated D-dimer and reduced von Willebrand factor activity, suggestive of endothelial dysfunction. In another case, BK virus reactivation was detected in a patient with PCP and hematuria, raising the possibility that latent viral reactivation contributes to the complexity of IRIS, though its pathogenetic role remains uncertain ( 20 – 22 ). These findings illustrate that IRIS can manifest as overlapping and multifactorial processes, complicating clinical management. Consistent with reports from Turkey, cryptococcal disease was a major contributor to mortality in advanced HIV ( 23 , 24 ). Mortality rates of 15–25% have been reported in African and Asian cohorts, whereas the 33.3% observed in our series likely reflects the effect of delayed presentation during the pandemic ( 25 , 26 ). Co-infections were also frequent, including syphilis (25%), HBV (33.3%), and HCV (8.3%). Only one case presented with fulminant hepatitis, and the small numbers limited definitive conclusions regarding their impact on outcomes. This study has limitations, including the small sample size, retrospective design, and single-center scope, which restrict generalizability. Limited access to advanced assays such as HHV-8 and cytokine profiling during the pandemic further constrained the assessment of immunopathogenesis. Nonetheless, the high incidence of IRIS and elevated mortality despite corticosteroid use emphasize the substantial challenges in managing advanced HIV ( 10 , 27 ). These observations align with global data showing that AIDS-related mortality remains disproportionately high among late presenters, reinforcing the need for multicenter, biomarker-driven prospective studies in this vulnerable group. Overall, our series suggests that IRIS in advanced HIV may represent an expected complication and a significant contributor to mortality. These findings underscore the urgent need to strengthen early diagnosis, enhance community awareness, and reduce stigma to prevent late presentations and improve outcomes ( 8 , 28 , 29 ). Conclusion This series demonstrates that delayed diagnosis and treatment, when combined with clustering of opportunistic infections and marked immuno-virological deterioration, substantially increased the risk of IRIS. Although the small sample size and retrospective design impose limitations, our findings indicate that IRIS in advanced HIV is not incidental but rather a predictable complication, underscoring the critical importance of strengthening early diagnosis programs, enhancing community awareness, and addressing stigma. Abbreviations HIV : Human Immunodeficiency Virus AIDS : Acquired Immunodeficiency Syndrome ART : Antiretroviral Therapy IRIS : Immune Reconstitution Inflammatory Syndrome PCP : Pneumocystis jirovecii Pneumonia CMV : Cytomegalovirus KS : Kaposi Sarcoma EBV : Epstein–Barr Virus HBV : Hepatitis B Virus HCV : Hepatitis C Virus WHO : World Health Organization CDC : Centers for Disease Control and Prevention EACS : European AIDS Clinical Society CSF : Cerebrospinal Fluid MRI : Magnetic Resonance Imaging CT : Computed Tomography RWS : AIDS-Related Wasting Syndrome TDF/FTC/DTG : Tenofovir Disoproxil Fumarate/Emtricitabine/Dolutegravir BIC/FTC/TAF : Bictegravir/Emtricitabine/Tenofovir Alafenamide SPSS : Statistical Package for the Social Sciences Declarations Ethics Approval: This study was approved by the Ethics Committee of Bursa City Hospital (Approval number: 2025-17/6, Date: 03.09.2025) and conducted in accordance with the principles of the Declaration of Helsinki. The requirement for informed consent was waived by the Ethics Committee due to the retrospective design and anonymized use of patient data, in accordance with national regulations. Consent for publication: Not applicable Availability of data and materials All data generated or analyzed during this study are included in this published article. The SPSS dataset can be provided by the corresponding author upon reasonable request. Funding: No funding was received for this study. Competing interests: The authors declare that they have no competing interests. Authors’ contributions: EG conceptualized and designed the study, collected clinical data, and drafted the manuscript. HO performed the statistical analysis. BT and VG contributed to data interpretation and critically revised the manuscript. All authors read and approved the final version of the manuscript. Acknowledgements: Not applicable References French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS. 2004 Aug 20;18(12):1615-27. DOI: 10.1097/01.aids.0000131375.21070.06 Battegay M, Fehr J, Flückiger U, Elzi L. Antiretroviral therapy of late presenters with advanced HIV disease. J Antimicrob Chemother. 2008 Jul;62(1):41-4. https://doi.org/10.1093/jac/dkn169 Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White AC, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS. 2005 Mar 4;19(4):399-406. Republic of Turkey, Ministry of Health, Public Health Institution of Turkey. HIV/AIDS Diagnosis and Treatment Guideline. Ankara: Ministry of Health Publications; 2013. Available from: https://hsgm.saglik.gov.tr/depo/birimler/bulasici-hastaliklar-ve-erken-uyari-db/Dokumanlar/Rehberler/HIV-AIDS_Tani-Tedavi_Rehberi_2013.pdf World Health Organization. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children. Geneva: WHO; 2007. Available from: https://iris.who.int/handle/10665/43699 Centers for Disease Control and Prevention. Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged <18 months and for HIV infection and AIDS among children aged 18 months to <13 years—United States, 2008. MMWR Recomm Rep. 2008;57(RR-10):1–8. Available from: https://www.cdc.gov/mmwr/pdf/rr/rr5710.pdf European AIDS Clinical Society. EACS Guidelines. Version 12.0. Brussels: EACS; 2023 [Internet]. Available from: https://www.eacsociety.org/guidelines Turkish HIV/AIDS Platform. HIV/AIDS Diagnosis, Monitoring and Treatment Handbook. 2nd ed. Istanbul: KLİMİK Society, EKMUD and collaborating societies; 2023. Available from: https://www.klimik.org.tr/wp-content/uploads/2023/01/HIVAIDS_El_Kitabi_Surum_2_.pdf Müller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10(4):251-61. DOI: 10.1016/S1473-3099(10)70026-8 Novak RM, Richardson JT, Buchacz K, Chmiel JS, Durham MD, Palella FJ, et al. Immune reconstitution inflammatory syndrome: incidence and implications for mortality. AIDS. 2012 Mar 27;26(6):721-30. https://doi.org/10.1097/QAD.0b013e3283511e91 Longley N, Harrison TS, Jarvis JN. Cryptococcal immune reconstitution inflammatory syndrome. Curr Opin Infect Dis. 2013 Feb;26(1):26-34. DOI: 10.1097/QCO.0b013e32835c21d1 Joint United Nations Programme on HIV/AIDS (UNAIDS). 2024 global AIDS report: The urgency of now—AIDS at a crossroads [Internet]. Geneva: UNAIDS; 2024. Available from: http://www.wipo.int/ World Health Organization. Patient monitoring guidelines for HIV care and antiretroviral therapy (ART) [Internet]. Geneva: World Health Organization; 2006 Availablefrom: https://apps.who.int/iris/handle/10665/43330 Grant PM, Komarow L, Andersen J, Sereti I, Pahwa S, Lederman MM, et al. Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection. PLoS One. 2010;5(7):e11416. https://doi.org/10.1371/journal.pone.0011416 Breton G, Duval X, Estellat C, Poaletti X, Bonnet D, Mvondo DM, et al. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis. 2004 Dec 1;39(11):1709-12. https://doi.org/10.1086/425742 Muthuka JK, Nyamai EM, Oluoch K, Maibvise C, Nabaweesi R. Paradoxical and unmasking HIV immune reconstitution inflammation syndrome in antiretroviral-naïve pregnant women: a prospective cohort study. Cureus. 2024 Jan 26;16(1):e54012. DOI: 10.7759/cureus.52989 Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010 Feb 25;362(8):697-706. DOI: 10.1056/NEJMoa1014181 Dutertre M, Cuzin L, Demonchy E, Puglièse P, Joly V, Valantin MA, et al. Initiation of antiretroviral therapy containing integrase inhibitors increases the risk of IRIS requiring hospitalization. J Acquir Immune Defic Syndr. 2017 Sep 1;76(1):e23-6. DOI: 10.1097/QAI.0000000000001397 Letang E, Lewis JJ, Bower M, Mosam A, Borok M, Campbell TB, et al. Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK. AIDS. 2013 Jun 19;27(10):1603-13. DOI: 10.1097/QAD.0b013e328360a5a1 Carbone A, Vaccher E, Gloghini A. Hematologic cancers in individuals infected by HIV. Blood. 2022 Feb 17;139(7):995-1012. https://doi.org/10.1016/S1525-1578(10)60004-9 Siedner MJ. START or SMART? Timing of antiretroviral therapy initiation and cardiovascular risk for people with human immunodeficiency virus infection. Open Forum Infect Dis. 2016 Jan 1;3(1):ofw032. https://doi.org/10.1093/ofid/ofw032 Jagannath S, Sachithanandham J, Ramalingam VV, Demosthenes JP, Abraham AM, Zachariah A, et al. BK virus characterisation among HIV-1-infected individuals and its association with immunosuppression. Indian J Med Microbiol. 2018 Apr 1;36(2):172-7. https://doi.org/10.4103/ijmm.IJMM_18_54 Küscu F, Bıkmaz AÇ, İlkit M, Karakoyun AS, Candevir A, Kömür S, et al. Cryptococcus antigen positivity in newly diagnosed HIV-positive individuals: a retrospective evaluation with the lateral flow method. Flora J Infect Dis Clin Microbiol. 2024 Dec 26;29(4):526-33. doi:10.5578/flora.2024041274 Gopal R, Rapaka RR, Kolls JK. Immune reconstitution inflammatory syndrome associated with pulmonary pathogens. Eur Respir Rev. 2017;26(145):170036. https://doi.org/10.1183/16000617.0042-2016 Lawn SD, Bekker LG, Myer L, Orrell C, Wood R. Cryptococcal immune reconstitution disease: a major cause of early mortality in a South African antiretroviral programme. AIDS. 2005;19(17):2050-2. DOI: 10.1097/01.aids.0000238406.93249.cd Wong CS, Wei L, Kim Y-S. HIV late presenters in Asia: management and public health challenges. AIDS Res Treat. 2023;2023:9488051. doi:10.1155/2023/9488051. PMID: 37351535; PMCID: PMC10284655. Aysert Yıldız P, Karamanlıoğlu D, Özger HS, Katı H, Güzel Tunçcan Ö, Dizbay M. Extrapulmonary tuberculosis: clinical and diagnostic features and risk factors for early mortality. Acta Med. 2022 Dec 25;53(4):367-74. DOI: https://doi.org/10.32552/2022.ActaMedica.844 Lodi S, Del Amo J, Moreno S, Bucher HC, Furrer H, Logan R, et al. Opportunistic infections and AIDS malignancies early after initiating combination antiretroviral therapy in high-income countries. AIDS. 2014 Dec 1;28(16):2461-73 https://doi.org/10.1093/cid/cir494 Grossman CI, Stangl AL. Global action to reduce HIV stigma and discrimination. J Int AIDS Soc. 2013 Nov 13;16(3 Suppl 2):18881. https://doi.org/10.7448/IAS.16.3.18881 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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-7742557","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":542150380,"identity":"15971ddd-b71d-419e-8b7a-fac0aa278f13","order_by":0,"name":"Emel Gurcuoglu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYHACxgOMDQwM/MzMB4AcCRmi9IC1SLazJYC08BCvxeA8jwGIQ1gLv9jhAwd/7rDJMzjM8/nVjRoLHgb2w0c34NMiOTst4TDvmbRiycO826xzjgEdxpOWdgOfFoPbOQaHGdsOJ/YBtRjnsAG1SPCY4dVifzv/w8Gfbf8TGw7zPDPO+UeEFgPpHIYDvG0HEicc5mF+nNtGhBaJ22kGh3nbkhNnNrOZMef2SfCwEfIL/+zkhw9/ttkl9vMffvw551udHD/74WN4tSADNgkwSaxyEGD+QIrqUTAKRsEoGDkAALaXTCYEsJnTAAAAAElFTkSuQmCC","orcid":"","institution":"Bursa City Hospital","correspondingAuthor":true,"prefix":"","firstName":"Emel","middleName":"","lastName":"Gurcuoglu","suffix":""},{"id":542150382,"identity":"88c0f45e-b276-4619-bff3-824ef4fc6b55","order_by":1,"name":"Bilge Tuna","email":"","orcid":"","institution":"Bursa City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bilge","middleName":"","lastName":"Tuna","suffix":""},{"id":542150384,"identity":"77593d17-6124-47af-ab7f-79a029b42a74","order_by":2,"name":"Hatice Ortac","email":"","orcid":"","institution":"Uludağ University, Institute of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Hatice","middleName":"","lastName":"Ortac","suffix":""},{"id":542150385,"identity":"3a61e085-9b7c-48a0-9959-f54fe8a839de","order_by":3,"name":"Vildan Gursoy","email":"","orcid":"","institution":"Bursa Uludağ University","correspondingAuthor":false,"prefix":"","firstName":"Vildan","middleName":"","lastName":"Gursoy","suffix":""}],"badges":[],"createdAt":"2025-09-29 13:23:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7742557/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7742557/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":95654915,"identity":"ba8434f2-187c-45a0-8f9c-c17ba311176d","added_by":"auto","created_at":"2025-11-11 16:13:47","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":59532,"visible":true,"origin":"","legend":"","description":"","filename":"07.10.2025HIVBMJMANUSCRIPT.docx","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/54e9ad3319ba7bfaf7a8cd08.docx"},{"id":95567352,"identity":"d1c600e2-f2a0-4c84-a579-f7ecd42131f6","added_by":"auto","created_at":"2025-11-10 16:22:46","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10221,"visible":true,"origin":"","legend":"","description":"","filename":"Resim2a.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/28a5305d119682c4e97a411c.jpg"},{"id":95655089,"identity":"372cb763-8014-42cc-8967-382d5a8cf6f9","added_by":"auto","created_at":"2025-11-11 16:14:17","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":347250,"visible":true,"origin":"","legend":"","description":"","filename":"Resim1.png","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/49e8b342ae757872db9cecea.png"},{"id":95655378,"identity":"7475d96a-00a4-4b1b-ba4c-1a34ffd69a98","added_by":"auto","created_at":"2025-11-11 16:15:48","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":15360,"visible":true,"origin":"","legend":"","description":"","filename":"Resim2b.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/79241c141d638c47c736b1e8.jpg"},{"id":95567358,"identity":"295d419d-3629-45bf-aca8-b1609a05e94e","added_by":"auto","created_at":"2025-11-10 16:22:46","extension":"json","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6120,"visible":true,"origin":"","legend":"","description":"","filename":"a76f0b7365ef4e529900a08848a71689.json","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/8df4347ee1ba847d86c6aa12.json"},{"id":95655565,"identity":"9b822d8f-7e23-4afb-be4e-d6436d964ff5","added_by":"auto","created_at":"2025-11-11 16:16:28","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":94036,"visible":true,"origin":"","legend":"","description":"","filename":"a76f0b7365ef4e529900a08848a716891enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/7f1b00f5c7bc62285edc3344.xml"},{"id":95655505,"identity":"4a466069-bbc5-4ae4-912e-05e01ed15928","added_by":"auto","created_at":"2025-11-11 16:16:21","extension":"jpg","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10221,"visible":true,"origin":"","legend":"","description":"","filename":"Resim2a.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/d73fe2f421203f960de759f2.jpg"},{"id":95567363,"identity":"e186858c-c236-49c7-bd69-e3dac653e5d3","added_by":"auto","created_at":"2025-11-10 16:22:47","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":347250,"visible":true,"origin":"","legend":"","description":"","filename":"Resim1.png","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/8c78bf6441532f696d505738.png"},{"id":95567354,"identity":"492ce90a-ba03-4b16-ba12-a083b09d5480","added_by":"auto","created_at":"2025-11-10 16:22:46","extension":"jpg","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":15360,"visible":true,"origin":"","legend":"","description":"","filename":"Resim2b.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/8a70ca54743221cf56eb73e8.jpg"},{"id":95567365,"identity":"e52ad629-c6cf-495a-ae97-a56b915e7722","added_by":"auto","created_at":"2025-11-10 16:22:47","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7965,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineResim2a.png","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/373a2e7d570f2b00594849fc.png"},{"id":95655562,"identity":"a6d28a7f-32c2-415d-b001-fe8a0fc9c768","added_by":"auto","created_at":"2025-11-11 16:16:28","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":60578,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineResim1.png","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/d53d6c36e95a3d4ea6ee6516.png"},{"id":95567362,"identity":"2338cd1e-4ce3-4192-ba19-be0fe0eaf6a9","added_by":"auto","created_at":"2025-11-10 16:22:47","extension":"png","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10486,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineResim2b.png","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/c283f6d4550ce1c8d2cc6495.png"},{"id":95567366,"identity":"0a3d90c1-5769-46a4-8303-40bc276db10f","added_by":"auto","created_at":"2025-11-10 16:22:47","extension":"xml","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":92000,"visible":true,"origin":"","legend":"","description":"","filename":"a76f0b7365ef4e529900a08848a716891structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/c4bbd06e9d06aa82a1d1be1e.xml"},{"id":95567367,"identity":"61a8a7df-7353-4acb-b8db-d0731ca99aae","added_by":"auto","created_at":"2025-11-10 16:22:47","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":102306,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/c2bd515d2e09ad43469741d6.html"},{"id":95567351,"identity":"27949fe9-958f-40f9-81d5-9da9cb70ee86","added_by":"auto","created_at":"2025-11-10 16:22:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":33455,"visible":true,"origin":"","legend":"\u003cp\u003eSagittal magnetic resonance imaging (MRI) of a patient with cerebral toxoplasmosis. The circled area (Mean: 159.04; StdDev: 42.19; Area: 1,397.90 mm²) demonstrates a mass-like lesion. Typical features of cerebral toxoplasmosis, including ring-enhancing appearance and surrounding edema, are evident. Findings were consistent with cerebral toxoplasmosis.\u003c/p\u003e","description":"","filename":"Resim2a.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/2368b42ac48a147581eeb976.jpg"},{"id":95567360,"identity":"7a3c03b6-7301-4e2a-9412-39eb1b59c37d","added_by":"auto","created_at":"2025-11-10 16:22:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":347250,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea b\u003c/strong\u003e Chest radiograph (a) and thoracic computed tomography (b) of a patient with \u003cem\u003ePneumocystis jirovecii \u003c/em\u003epneumonia. The chest X-ray demonstrates bilateral diffuse interstitial infiltrates, while the CT scan reveals patchy ground-glass opacities predominantly in the perihilar regions, consistent with \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e infection in HIV.\u003c/p\u003e","description":"","filename":"Resim1.png","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/4a2e54cd23fc66f73fb43b51.png"},{"id":101849037,"identity":"823e9a1a-efba-47d5-8aba-4444d1b7cae9","added_by":"auto","created_at":"2026-02-04 09:43:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1263824,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7742557/v1/675d4fe3-b04f-4099-b035-322f638dfaef.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"IRIS and Mortality in Advanced HIV: Post-Pandemic Experience from a Single-Center Case Series","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe clinical course of HIV infection is determined by the interplay of several factors, including baseline immune reserve at diagnosis, the level of viral replication and antigenic burden, co-infections, and the timing of antiretroviral therapy (ART) initiation. While the introduction of ART has led to a marked reduction in opportunistic infections and AIDS-related malignancies, in some patients rapid immune recovery may trigger an exaggerated inflammatory response, thereby complicating the clinical course and contributing to increased morbidity and mortality (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Patients presenting with profound immunosuppression and high antigenic burden are at particularly high risk for developing immune reconstitution inflammatory syndrome (IRIS), which substantially complicates clinical management (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe COVID-19 pandemic further disrupted timely access to HIV diagnosis and treatment, resulting in a greater proportion of patients presenting at advanced stages of disease and making IRIS more clinically visible. In the post-pandemic period, the increased frequency of IRIS among ART-na\u0026iuml;ve individuals with advanced HIV, together with its expanding clinical spectrum and its strong association with mortality, has emerged as one of the most critical challenges in current clinical practice (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis study presents the clinical experience of a tertiary care center with ART-na\u0026iuml;ve patients diagnosed with advanced HIV infection in the post-pandemic era. This 12-case series aims to describe the frequency and clinical subtypes of IRIS (unmasking and paradoxical), characterize its immunovirological dynamics, and assess its impact on survival, while also sharing insights into the clinical presentations and management strategies observed in late presenters.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThis retrospective case series included adult patients who presented with advanced HIV infection (CD4\u0026thinsp;\u0026lt;\u0026thinsp;200 cells/mm\u0026sup3; and/or presence of an AIDS-defining condition) and were followed at our tertiary care center during the post-pandemic period (2021\u0026ndash;2025). Eligibility criteria required available baseline data including CD4 count, CD4/CD8 ratio, and HIV RNA level at diagnosis. Cases with documented secondary infections or drug reactions were included.\u003c/p\u003e\u003cp\u003eExclusion criteria were: prior or ongoing ART exposure at presentation, incomplete follow-up records precluding IRIS evaluation, acute HIV infection without advanced disease criteria, and pediatric age (\u0026lt;\u0026thinsp;18 years).\u003c/p\u003e\u003cp\u003eThe following parameters were recorded: demographic data, date of HIV diagnosis and ART initiation, ART regimen, baseline CD4 count, CD4/CD8 ratio, HIV RNA level, and presence of opportunistic infections, AIDS-related malignancies, or autoimmune conditions. During follow-up, IRIS occurrence, subtype (unmasking or paradoxical), time to onset, CD4 count and HIV RNA level at IRIS, and use of systemic corticosteroids were documented. Additional data included co-infections (HBV, HCV, syphilis), EBV serology, most recent CD4/CD8 ratio, last available HIV RNA level, and survival status.\u003c/p\u003e\u003cp\u003eThe classification of opportunistic infections and AIDS-defining conditions, as well as IRIS evaluation, was based on the World Health Organization (WHO) clinical staging system and the Centers for Disease Control and Prevention (CDC) AIDS case definition (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). IRIS was defined as the clinical manifestation of a previously undiagnosed opportunistic infection (unmasking IRIS) or the unexpected worsening of a known infection (paradoxical IRIS) following ART initiation and immune recovery. Confirmation required evidence of virological response, with alternative explanations such as new infections, natural disease progression, or drug toxicity excluded. In cases without laboratory confirmation, diagnosis was established through multidisciplinary clinical consensus.\u003c/p\u003e\u003cp\u003eDiagnostic confirmation for specific conditions required: clinical suspicion supported by chest CT findings and positive immunofluorescence for \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e pneumonia (PCP) Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb).; culture, molecular methods, or histopathology for tuberculosis; cerebrospinal fluid molecular analysis for central nervous system toxoplasmosis; and blood and/or CSF culture positivity for cryptococcosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Malignancies and dermatological lesions required histopathological reports, while gastrointestinal infections required endoscopic findings supported by culture, molecular, and/or histopathology.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTreatment responses were reclassified according to the 2023 European AIDS Clinical Society (EACS) guidelines (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Virological response was categorized as full suppression (HIV RNA\u0026thinsp;\u0026lt;\u0026thinsp;50 copies/mL), partial suppression (significant log reduction with persistent detectability), or failure (no suppression or viral rebound). Immunological response was defined as an increase of at least 50\u0026ndash;100 cells/mm\u0026sup3; in CD4 count within the first year, as recommended by the guidelines.\u003c/p\u003e\u003cp\u003eOne patient who could not initiate ART due to early mortality and another with incomplete immunovirological data were excluded from IRIS subtype and CD4/HIV RNA dynamic analyses but remained included in survival and mortality evaluations.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eNormality of distribution for continuous variables was assessed using the Shapiro\u0026ndash;Wilk test. Variables with normal distribution were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and those without normal distribution as median (minimum\u0026ndash;maximum). Categorical variables were expressed as n (%). Statistical analyses were performed using SPSS software (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.), with a type I error threshold of 5%.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFor descriptive analyses, median values were preferred for variables with wide biological dispersion (e.g., CD4 count, HIV RNA level) to more accurately reflect central tendency and minimize the impact of outliers. According to CDC and WHO classifications, the majority of patients were in CDC stage 3 / WHO stage 4 (AIDS stage) at diagnosis, while only 1\u0026ndash;2 patients had CD4 counts between 200\u0026ndash;286/mm\u0026sup3;, corresponding to CDC stage 2 / WHO stage 3 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe mean age was 42.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8 years, with a median of 45.5 (range: 21\u0026ndash;61). Ten patients (83.3%) were male and two (16.7%) female. The mean time from diagnosis to ART initiation was 12.2\u0026thinsp;\u0026plusmn;\u0026thinsp;28.3 days, with a median of 0 (0\u0026ndash;88). One patient had remained untreated from diagnosis in 2017 until 2023, and another with cryptococcal sepsis and meningitis had died before ART initiation (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline clinical and laboratory characteristics of the study cohort (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eValue\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42.17\u0026thinsp;\u0026plusmn;\u0026thinsp;13.81; median 45.5 (21\u0026ndash;61)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale: 2 (16.7%), Male: 10 (83.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTime from HIV diagnosis to ART initiation (days)\u003c/b\u003e *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12.20\u0026thinsp;\u0026plusmn;\u0026thinsp;28.34; median 0 (0\u0026ndash;88)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIRIS\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresent: 11 (91.7%), Absent: 1 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTime from ART to IRIS (days)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e71.09\u0026thinsp;\u0026plusmn;\u0026thinsp;59.57; median 49 (20\u0026ndash;213)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eType of IRIS\u003c/b\u003e**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnmasking: 7/11 (63.6%), Paradoxical: 4/11 (36.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSystemic corticosteroid use\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOverall: 8/12 (66.7%);\u0026nbsp;IRIS-related: 7/11 (63.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBaseline CD4 (cells/mm\u0026sup3;)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.79\u0026thinsp;\u0026plusmn;\u0026thinsp;103.09; median 52.88 (9.09\u0026ndash;286)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBaseline CD4/CD8 ratio\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15; median 0.12 (0.02\u0026ndash;0.53)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBaseline HIV RNA (copies/mL)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5,675,183\u0026thinsp;\u0026plusmn;\u0026thinsp;5,706,394.82; median 3,824,224 (90,813\u0026ndash;14,491,703)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCD4 at IRIS (cells/mm\u0026sup3;)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e310.10\u0026thinsp;\u0026plusmn;\u0026thinsp;213.79; median 279.5 (40\u0026ndash;635)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHIV RNA at IRIS (copies/mL)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45,095.3\u0026thinsp;\u0026plusmn;\u0026thinsp;128,481.75; median 2,883.5 (34\u0026ndash;410,471)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLast follow-up CD4 (cells/mm\u0026sup3;)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e382.18\u0026thinsp;\u0026plusmn;\u0026thinsp;254.82; median 325.5 (73\u0026ndash;910)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLast follow-up CD4/CD8 ratio\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.32; median 0.57 (0\u0026ndash;1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLast follow-up HIV RNA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUndetectable: 5/12 (41.7%); Detectable: median 190 (103\u0026ndash;821)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eART regimen\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo ART: 1 (8.3%); TDF/FTC/DTG: 7 (58.3%);\u0026nbsp;BIC/FTC/TAF: 4 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCo-infections\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eSyphilis\u003c/em\u003e: 3 (25%); EBV positive: 8 (66.7%); HBV: 4 (33.3%); HCV: 1 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSurvival\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDeath: 4 (33.3%), Alive: 8 (66.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003e* One patient with lymphoma was diagnosed with HIV in 2017 but remained untreated until 2023; this case was not included in the statistical calculations and is therefore not reflected in the \u0026ldquo;Time from HIV diagnosis to ART initiation\u0026rdquo; values.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003e** Percentages for IRIS subtypes are calculated based on the 11 patients who started ART and developed IRIS.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIRIS developed in all 11 patients (100%) who received ART, while the patient who died prior to ART initiation was excluded from IRIS analyses. The mean time from ART initiation to IRIS onset was 71.1\u0026thinsp;\u0026plusmn;\u0026thinsp;59.6 days, with a median of 49 (20\u0026ndash;213). Unmasking IRIS was the predominant subtype (63.6%, n\u0026thinsp;=\u0026thinsp;7), followed by paradoxical IRIS (36.4%, n\u0026thinsp;=\u0026thinsp;4). IRIS subtypes and associated AIDS-defining illnesses were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAIDS-defining conditions and associated types of IRIS\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAIDS-defining condition\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eType of IRIS\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eCryptococcal\u003c/em\u003e infection\u0026thinsp;+\u0026thinsp;AIDS-RWS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDeath (ART not initiated)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisseminated herpes zoster\u0026thinsp;+\u0026thinsp;AIDS-RWS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnmasking(Unm) CMV colitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOropharyngeal candidiasis\u0026thinsp;+\u0026thinsp;AIDS-RWS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnm. CMV retinitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003ePneumocystis jirovecii\u003c/em\u003e pneumonia\u0026thinsp;+\u0026thinsp;AIDS-RWS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eParadoxical (Par)P. jirovecii pneumonia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePersistent lymphadenopathy\u0026thinsp;+\u0026thinsp;atypical pneumonia\u0026thinsp;+\u0026thinsp;AIDS-RWS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnm. lymphoma\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAIDS-RWS\u0026thinsp;+\u0026thinsp;vaginal candidiasis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnm. lymphoma\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCNS toxoplasmosis\u0026thinsp;+\u0026thinsp;AIDS-RWS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePar.cutaneous IRIS\u0026thinsp;+\u0026thinsp;Unm Candida esophagitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMiliary tuberculosis\u0026thinsp;+\u0026thinsp;AIDS-RWS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePar. tuberculosis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRecurrent pneumonia\u0026thinsp;+\u0026thinsp;seborrheic dermatitis\u0026thinsp;+\u0026thinsp;AIDS-RWS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnm tuberculosis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisseminated herpes zoster\u0026thinsp;+\u0026thinsp;persistent lymphadenopathy\u0026thinsp;+\u0026thinsp;AIDS-RWS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePar. HPV-related lesions\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKaposi\u0026rsquo;s sarcoma\u0026thinsp;+\u0026thinsp;oropharyngeal candidiasis\u0026thinsp;+\u0026thinsp;AIDS-RWS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePar. Kaposi\u0026rsquo;s sarcoma\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOropharyngeal candidiasis\u0026thinsp;+\u0026thinsp;AIDS-RWS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnm. Kaposi\u0026rsquo;s sarcoma\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cb\u003eAIDS-RWS\u003c/b\u003e (AIDS-related wasting syndrome) is defined as \u0026ge;\u0026thinsp;10% unintentional weight loss associated with \u0026ge;\u0026thinsp;30 days of diarrhea or fever.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSystemic corticosteroids were administered to 8 patients (66.7%); however, in one case steroids were used for cryptococcal meningitis prior to ART and were unrelated to IRIS. Thus, 7 of 11 patients (63.6%) received steroids for IRIS management. Steroid therapy was not required in cases of CMV colitis, CMV retinitis, paradoxical HPV, or unmasking tuberculosis. In patients treated with steroids, the median CD4 count increased from 84 cells/mm\u0026sup3; at diagnosis to 266 cells/mm\u0026sup3; during IRIS (mean 2.6-fold rise; range: 1.1\u0026ndash;16.6), while median HIV RNA decreased from 3.6 \u0026times; 10⁶ copies/mL to 7.9 \u0026times; 10\u0026sup3; copies/mL, representing a mean decline of 2.7 log₁₀ (range: 0.95\u0026ndash;3.73). Among the 7 patients receiving steroids for IRIS, three (42.9%) died and four survived. Patient-level changes in CD4 count, HIV RNA decline, and survival status were detailed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eImmunological and virological changes and survival among patients receiving corticosteroids\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatients receiving steroids\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCD4 fold increase\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHIV RNA log₁₀ decline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSurvival\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eCryptococcal\u003c/em\u003e sepsis\u0026thinsp;+\u0026thinsp;meningitis*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDeath\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eP. jirovecii\u003c/em\u003e\u0026nbsp;pneumonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDeath\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCNS Lymphoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlive\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLymphoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlive\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSeborrheic dermatitis\u0026thinsp;+\u0026thinsp;Candida esophagitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlive\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMiliary Tuberculosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAlive\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKaposi\u0026rsquo;s sarcoma*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDeath\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKaposi\u0026rsquo;s sarcoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDeath\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e* In the cryptococcal meningitis case, corticosteroids were administered before ART initiation and were therefore not related to IRIS. In one Kaposi\u0026rsquo;s sarcoma case, no laboratory confirmation was available during the suspected IRIS episode; the diagnosis was based on clinical and radiological findings\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAt baseline, the mean CD4 count was 99.8\u0026thinsp;\u0026plusmn;\u0026thinsp;103.1/mm\u0026sup3;, with a median of 52.9 (9.1\u0026ndash;286). The CD4/CD8 ratio averaged 0.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15 (median 0.12), reflecting profound immunodeficiency. The mean HIV RNA was 5,675,183\u0026thinsp;\u0026plusmn;\u0026thinsp;5,706,395 copies/mL, with a median of 3,824,224 (90,813\u0026ndash;14,491,703). During IRIS, the mean CD4 count rose to 310.1\u0026thinsp;\u0026plusmn;\u0026thinsp;213.8/mm\u0026sup3; (median 279.5; 40\u0026ndash;635), while median HIV RNA declined to 2,883 copies/mL (34\u0026ndash;410,471). At the last follow-up, the mean CD4 count was 382.2\u0026thinsp;\u0026plusmn;\u0026thinsp;254.8/mm\u0026sup3; (median 325.5; 73\u0026ndash;910), and the CD4/CD8 ratio was 0.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.32 (median 0.57). HIV RNA was undetectable in 41.7% of patients; among those with detectable viremia, the median level was 190 copies/mL (103\u0026ndash;821).\u003c/p\u003e\u003cp\u003eOverall, IRIS occurred in 11 of 12 patients (91.7%). The distribution of subtypes mirrored earlier findings, with unmasking IRIS accounting for 63.6% (n\u0026thinsp;=\u0026thinsp;7) and paradoxical IRIS for 36.4% (n\u0026thinsp;=\u0026thinsp;4). Corticosteroids were administered in 8 patients (66.7%), but only 7 cases were IRIS-related (63.6% of those starting ART). At the end of follow-up, overall survival was 66.7% (n\u0026thinsp;=\u0026thinsp;8), while 33.3% (n\u0026thinsp;=\u0026thinsp;4) died during the IRIS course. Baseline and follow-up clinical and laboratory features were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eAccording to the 2023 EACS criteria, treatment responses were heterogeneous. Complete virological suppression was achieved in five patients (Cases 2, 3, 5, 6, 10), while three (Cases 7, 8, 9) had partial responses (HIV RNA decline\u0026thinsp;\u0026gt;\u0026thinsp;1\u0026ndash;2 log₁₀ but remained detectable). Four patients (Cases 1, 4, 11, 12) experienced virological failure, with fatalities occurring particularly among those with PCP and KS. Immunologically, most patients met the EACS criterion of a\u0026thinsp;+\u0026thinsp;50\u0026ndash;100 cells/mm\u0026sup3; CD4 increase within the first year (e.g., Case 5: 267 to 910/mm\u0026sup3;), though recovery was insufficient in some (Cases 4 and 11) and was associated with mortality.\u003c/p\u003e\u003cp\u003eAmong ART regimens, 7 patients (58.3%) received TDF/FTC/DTG, 4 (33.3%) BIC/FTC/TAF, and 1 remained untreated (8.3%). Among the 11 patients who initiated ART, virological and/or immunological response was achieved in 72.7% (n\u0026thinsp;=\u0026thinsp;8), while 27.3% (n\u0026thinsp;=\u0026thinsp;3) remained non-responders. EBV seropositivity was found in 66.7%, negative in 16.7%, and not tested in 16.7%. Co-infections included syphilis in 25% (n\u0026thinsp;=\u0026thinsp;3), HBV in 33.3% (n\u0026thinsp;=\u0026thinsp;4), and HCV in 8.3% (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e\u003cp\u003eDuring follow-up, four patients (33.3%) died and eight (66.7%) survived (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). One patient died before ART could be initiated.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study describes the experience of a small cohort of ART-na\u0026iuml;ve patients with advanced HIV and offers additional insights into the biological and clinical spectrum of IRIS. Our findings suggest that delayed diagnosis and high antigen burden appeared to increase the risk of IRIS and AIDS-related mortality (\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Although international data suggest a decline in mortality, the 33.3% case-fatality rate in our cohort\u0026mdash;comprising exclusively advanced cases\u0026mdash;was higher than the 10\u0026ndash;20% reported in previous studies (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). These results underscore the critical impact of late presentation and highlight the importance of strengthening early diagnostic programs and addressing stigma as essential components of HIV care.\u003c/p\u003e\u003cp\u003eAt baseline, a median CD4 count of 52.9/mm\u0026sup3;, CD4/CD8 ratio of 0.12, and HIV RNA level of 3.8 \u0026times; 10⁶ copies/mL reflected profound immunodeficiency, consistent with advanced-stage disease. During follow-up, a 5.3-fold increase in CD4 count and a 3.1 log decline in HIV RNA demonstrated the simultaneous occurrence of rapid immune reconstitution and viral suppression, in line with existing evidence on the pathogenesis of IRIS (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn our series, unmasking IRIS was the most frequent presentation (63.6%), followed by paradoxical forms (36.4%), a distribution comparable to reports from other advanced cohorts (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). The relatively high proportion of unmasking IRIS likely reflected pandemic-related diagnostic delays and elevated antigen burden. The wide onset interval (20\u0026ndash;213 days) emphasized that IRIS may arise throughout the treatment course and underscored the need for prolonged vigilance in advanced cases.\u003c/p\u003e\u003cp\u003eNo clear differences in outcomes were observed between patients receiving TDF/FTC/DTG and those on BIC/FTC/TAF. However, the lack of virological or immunological response in one-third of patients suggests that treatment success depended less on regimen choice than on baseline conditions\u0026mdash;namely late diagnosis, high burden of opportunistic infections, and severe immunosuppression (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eSystemic corticosteroids were required in approximately two-thirds of cases. Nevertheless, patients with CMV colitis, CMV retinitis, paradoxical HPV, or unmasking tuberculosis did not require steroids, indicating that IRIS severity was shaped not only by immune recovery but also by antigen load, site of involvement, and host-specific immune responses (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Although steroid-treated patients showed a median 2.6-fold CD4 increase and 2.7 log₁₀ HIV RNA decline, survival in this group was only 57.1%, suggesting that corticosteroids alone were insufficient in advanced cases with high antigen burden. Larger, prospective studies are needed to clarify their impact on survival (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eNotable clinical observations further highlighted the heterogeneity of IRIS. One patient with unmasking EBV-associated lymphoma presented with hemostatic abnormalities, including elevated D-dimer and reduced von Willebrand factor activity, suggestive of endothelial dysfunction. In another case, BK virus reactivation was detected in a patient with PCP and hematuria, raising the possibility that latent viral reactivation contributes to the complexity of IRIS, though its pathogenetic role remains uncertain (\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). These findings illustrate that IRIS can manifest as overlapping and multifactorial processes, complicating clinical management.\u003c/p\u003e\u003cp\u003eConsistent with reports from Turkey, cryptococcal disease was a major contributor to mortality in advanced HIV (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Mortality rates of 15\u0026ndash;25% have been reported in African and Asian cohorts, whereas the 33.3% observed in our series likely reflects the effect of delayed presentation during the pandemic (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Co-infections were also frequent, including syphilis (25%), HBV (33.3%), and HCV (8.3%). Only one case presented with fulminant hepatitis, and the small numbers limited definitive conclusions regarding their impact on outcomes.\u003c/p\u003e\u003cp\u003eThis study has limitations, including the small sample size, retrospective design, and single-center scope, which restrict generalizability. Limited access to advanced assays such as HHV-8 and cytokine profiling during the pandemic further constrained the assessment of immunopathogenesis. Nonetheless, the high incidence of IRIS and elevated mortality despite corticosteroid use emphasize the substantial challenges in managing advanced HIV (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). These observations align with global data showing that AIDS-related mortality remains disproportionately high among late presenters, reinforcing the need for multicenter, biomarker-driven prospective studies in this vulnerable group.\u003c/p\u003e\u003cp\u003eOverall, our series suggests that IRIS in advanced HIV may represent an expected complication and a significant contributor to mortality. These findings underscore the urgent need to strengthen early diagnosis, enhance community awareness, and reduce stigma to prevent late presentations and improve outcomes (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis series demonstrates that delayed diagnosis and treatment, when combined with clustering of opportunistic infections and marked immuno-virological deterioration, substantially increased the risk of IRIS. Although the small sample size and retrospective design impose limitations, our findings indicate that IRIS in advanced HIV is not incidental but rather a predictable complication, underscoring the critical importance of strengthening early diagnosis programs, enhancing community awareness, and addressing stigma.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eHIV\u003c/strong\u003e: Human Immunodeficiency Virus\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAIDS\u003c/strong\u003e: Acquired Immunodeficiency Syndrome\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eART\u003c/strong\u003e: Antiretroviral Therapy\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eIRIS\u003c/strong\u003e: Immune Reconstitution Inflammatory Syndrome\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePCP\u003c/strong\u003e: \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e Pneumonia\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCMV\u003c/strong\u003e: Cytomegalovirus\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eKS\u003c/strong\u003e: Kaposi Sarcoma\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eEBV\u003c/strong\u003e: Epstein\u0026ndash;Barr Virus\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eHBV\u003c/strong\u003e: Hepatitis B Virus\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eHCV\u003c/strong\u003e: Hepatitis C Virus\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eWHO\u003c/strong\u003e: World Health Organization\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCDC\u003c/strong\u003e: Centers for Disease Control and Prevention\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eEACS\u003c/strong\u003e: European AIDS Clinical Society\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCSF\u003c/strong\u003e: Cerebrospinal Fluid\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMRI\u003c/strong\u003e: Magnetic Resonance Imaging\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCT\u003c/strong\u003e: Computed Tomography\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eRWS\u003c/strong\u003e: AIDS-Related Wasting Syndrome\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTDF/FTC/DTG\u003c/strong\u003e: Tenofovir Disoproxil Fumarate/Emtricitabine/Dolutegravir\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eBIC/FTC/TAF\u003c/strong\u003e: Bictegravir/Emtricitabine/Tenofovir Alafenamide\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSPSS\u003c/strong\u003e: Statistical Package for the Social Sciences\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval:\u003c/strong\u003e\u003cbr\u003eThis study was approved by the Ethics Committee of Bursa City Hospital (Approval number: 2025-17/6, Date: 03.09.2025) \u003cstrong\u003eand\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;conducted in accordance with the principles of the Declaration of Helsinki. The requirement for informed consent was waived by the Ethics Committee due to the retrospective design and anonymized use of patient data, in accordance with national regulations.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003cbr\u003eAll data generated or analyzed during this study are included in this published article. The SPSS dataset can be provided by the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests.\u003cbr\u003e\u003cstrong\u003eAuthors’ contributions:\u003c/strong\u003e EG conceptualized and designed the study, collected clinical data, and drafted the manuscript. HO performed the statistical analysis. BT and VG contributed to data interpretation and critically revised the manuscript. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFrench MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS. 2004 Aug 20;18(12):1615-27. \u003cem\u003eDOI:\u003c/em\u003e 10.1097/01.aids.0000131375.21070.06\u003c/li\u003e\n\u003cli\u003eBattegay M, Fehr J, Fl\u0026uuml;ckiger U, Elzi L. Antiretroviral therapy of late presenters with advanced HIV disease. J Antimicrob Chemother. 2008 Jul;62(1):41-4. https://doi.org/10.1093/jac/dkn169\u003c/li\u003e\n\u003cli\u003eShelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White AC, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS. 2005 Mar 4;19(4):399-406.\u003c/li\u003e\n\u003cli\u003eRepublic of Turkey, Ministry of Health, Public Health Institution of Turkey. HIV/AIDS Diagnosis and Treatment Guideline. Ankara: Ministry of Health Publications; 2013. Available from: https://hsgm.saglik.gov.tr/depo/birimler/bulasici-hastaliklar-ve-erken-uyari-db/Dokumanlar/Rehberler/HIV-AIDS_Tani-Tedavi_Rehberi_2013.pdf\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. \u003cem\u003eWHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children.\u003c/em\u003e Geneva: WHO; 2007. Available from: https://iris.who.int/handle/10665/43699\u003c/li\u003e\n\u003cli\u003eCenters for Disease Control and Prevention. Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged \u0026lt;18 months and for HIV infection and AIDS among children aged 18 months to \u0026lt;13 years\u0026mdash;United States, 2008. \u003cem\u003eMMWR Recomm Rep.\u003c/em\u003e 2008;57(RR-10):1\u0026ndash;8. Available from: https://www.cdc.gov/mmwr/pdf/rr/rr5710.pdf\u003c/li\u003e\n\u003cli\u003eEuropean AIDS Clinical Society. EACS Guidelines. Version 12.0. Brussels: EACS; 2023 [Internet]. Available from: https://www.eacsociety.org/guidelines\u003c/li\u003e\n\u003cli\u003eTurkish HIV/AIDS Platform. HIV/AIDS Diagnosis, Monitoring and Treatment Handbook. 2nd ed. Istanbul: KLİMİK Society, EKMUD and collaborating societies; 2023. Available from: https://www.klimik.org.tr/wp-content/uploads/2023/01/HIVAIDS_El_Kitabi_Surum_2_.pdf\u003c/li\u003e\n\u003cli\u003eM\u0026uuml;ller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10(4):251-61. DOI: 10.1016/S1473-3099(10)70026-8\u003c/li\u003e\n\u003cli\u003eNovak RM, Richardson JT, Buchacz K, Chmiel JS, Durham MD, Palella FJ, et al. Immune reconstitution inflammatory syndrome: incidence and implications for mortality. AIDS. 2012 Mar 27;26(6):721-30. https://doi.org/10.1097/QAD.0b013e3283511e91\u003c/li\u003e\n\u003cli\u003eLongley N, Harrison TS, Jarvis JN. Cryptococcal immune reconstitution inflammatory syndrome. Curr Opin Infect Dis. 2013 Feb;26(1):26-34. DOI: 10.1097/QCO.0b013e32835c21d1\u003c/li\u003e\n\u003cli\u003eJoint United Nations Programme on HIV/AIDS (UNAIDS). 2024 global AIDS report: The urgency of now\u0026mdash;AIDS at a crossroads [Internet]. Geneva: UNAIDS; 2024. Available from: http://www.wipo.int/\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. Patient monitoring guidelines for HIV care and antiretroviral therapy (ART) [Internet]. Geneva: World Health Organization; 2006 Availablefrom: https://apps.who.int/iris/handle/10665/43330\u003c/li\u003e\n\u003cli\u003eGrant PM, Komarow L, Andersen J, Sereti I, Pahwa S, Lederman MM, et al. Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection. PLoS One. 2010;5(7):e11416. https://doi.org/10.1371/journal.pone.0011416\u003c/li\u003e\n\u003cli\u003eBreton G, Duval X, Estellat C, Poaletti X, Bonnet D, Mvondo DM, et al. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis. 2004 Dec 1;39(11):1709-12. https://doi.org/10.1086/425742\u003c/li\u003e\n\u003cli\u003eMuthuka JK, Nyamai EM, Oluoch K, Maibvise C, Nabaweesi R. Paradoxical and unmasking HIV immune reconstitution inflammation syndrome in antiretroviral-na\u0026iuml;ve pregnant women: a prospective cohort study. Cureus. 2024 Jan 26;16(1):e54012. DOI: 10.7759/cureus.52989\u003c/li\u003e\n\u003cli\u003eAbdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010 Feb 25;362(8):697-706. DOI: 10.1056/NEJMoa1014181\u003c/li\u003e\n\u003cli\u003eDutertre M, Cuzin L, Demonchy E, Pugli\u0026egrave;se P, Joly V, Valantin MA, et al. Initiation of antiretroviral therapy containing integrase inhibitors increases the risk of IRIS requiring hospitalization. J Acquir Immune Defic Syndr. 2017 Sep 1;76(1):e23-6.\u003cem\u003e \u003c/em\u003e\u003cem\u003eDOI:\u003c/em\u003e 10.1097/QAI.0000000000001397\u003c/li\u003e\n\u003cli\u003eLetang E, Lewis JJ, Bower M, Mosam A, Borok M, Campbell TB, et al. Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK. AIDS. 2013 Jun 19;27(10):1603-13.\u003cem\u003e \u003c/em\u003e\u003cem\u003eDOI:\u003c/em\u003e 10.1097/QAD.0b013e328360a5a1\u003c/li\u003e\n\u003cli\u003eCarbone A, Vaccher E, Gloghini A. Hematologic cancers in individuals infected by HIV. Blood. 2022 Feb 17;139(7):995-1012. https://doi.org/10.1016/S1525-1578(10)60004-9\u003c/li\u003e\n\u003cli\u003eSiedner MJ. START or SMART? Timing of antiretroviral therapy initiation and cardiovascular risk for people with human immunodeficiency virus infection. Open Forum Infect Dis. 2016 Jan 1;3(1):ofw032. https://doi.org/10.1093/ofid/ofw032\u003c/li\u003e\n\u003cli\u003eJagannath S, Sachithanandham J, Ramalingam VV, Demosthenes JP, Abraham AM, Zachariah A, et al. BK virus characterisation among HIV-1-infected individuals and its association with immunosuppression. Indian J Med Microbiol. 2018 Apr 1;36(2):172-7. https://doi.org/10.4103/ijmm.IJMM_18_54\u003c/li\u003e\n\u003cli\u003eKüscu F, Bıkmaz A\u0026Ccedil;, İlkit M, Karakoyun AS, Candevir A, K\u0026ouml;m\u0026uuml;r S, et al. Cryptococcus antigen positivity in newly diagnosed HIV-positive individuals: a retrospective evaluation with the lateral flow method. Flora J Infect Dis Clin Microbiol. 2024 Dec 26;29(4):526-33. doi:10.5578/flora.2024041274 \u003c/li\u003e\n\u003cli\u003eGopal R, Rapaka RR, Kolls JK. Immune reconstitution inflammatory syndrome associated with pulmonary pathogens. Eur Respir Rev. 2017;26(145):170036. https://doi.org/10.1183/16000617.0042-2016\u003c/li\u003e\n\u003cli\u003eLawn SD, Bekker LG, Myer L, Orrell C, Wood R. Cryptococcal immune reconstitution disease: a major cause of early mortality in a South African antiretroviral programme. AIDS. 2005;19(17):2050-2.\u003cem\u003e \u003c/em\u003e\u003cem\u003eDOI:\u003c/em\u003e 10.1097/01.aids.0000238406.93249.cd\u003c/li\u003e\n\u003cli\u003eWong CS, Wei L, Kim Y-S. HIV late presenters in Asia: management and public health challenges. \u003cem\u003eAIDS Res Treat.\u003c/em\u003e2023;2023:9488051. doi:10.1155/2023/9488051. PMID: 37351535; PMCID: PMC10284655.\u003c/li\u003e\n\u003cli\u003eAysert Yıldız P, Karamanlıoğlu D, \u0026Ouml;zger HS, Katı H, G\u0026uuml;zel Tun\u0026ccedil;can \u0026Ouml;, Dizbay M. Extrapulmonary tuberculosis: clinical and diagnostic features and risk factors for early mortality. Acta Med. 2022 Dec 25;53(4):367-74. DOI: https://doi.org/10.32552/2022.ActaMedica.844\u003c/li\u003e\n\u003cli\u003eLodi S, Del Amo J, Moreno S, Bucher HC, Furrer H, Logan R, et al. Opportunistic infections and AIDS malignancies early after initiating combination antiretroviral therapy in high-income countries. AIDS. 2014 Dec 1;28(16):2461-73 https://doi.org/10.1093/cid/cir494\u003c/li\u003e\n\u003cli\u003eGrossman CI, Stangl AL. Global action to reduce HIV stigma and discrimination. J Int AIDS Soc. 2013 Nov 13;16(3 Suppl 2):18881. \u003cstrong\u003ehttps://doi.org/10.7448/IAS.16.3.18881\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HIV, advanced disease, immune reconstitution inflammatory syndrome, opportunistic infections, mortality","lastPublishedDoi":"10.21203/rs.3.rs-7742557/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7742557/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe aimed to retrospectively evaluate patients presenting with advanced human immunodeficiency virus (HIV) infection and AIDS-defining conditions following the pandemic, and to examine the occurrence of immune reconstitution inflammatory syndrome (IRIS) after antiretroviral therapy (ART) initiation. In addition, we sought to present our clinical experience.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials and Methods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween 2021 and 2025, we retrospectively reviewed 12 ART-naïve adults with advanced HIV infection and complete medical records. Demographic, immunological, and virological parameters, opportunistic infections, IRIS types, and treatment responses were recorded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIRIS developed in all 11 patients (100%) who initiated ART. The median time to IRIS onset was 49 days (range: 20–213). Unmasking IRIS occurred in 63.6% of cases, while paradoxical IRIS accounted for 36.4%. Clinical manifestations included tuberculosis, cytomegalovirus infection, cryptococcosis, toxoplasmosis, Kaposi sarcoma, and lymphoma. Corticosteroid therapy was required in 63.6% of patients. Overall mortality was 33.3%, most frequently associated with cryptococcal meningitis, Pneumocystis jirovecii pneumonia, and Kaposi sarcoma.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn our study, the high rates of IRIS and mortality observed among patients with advanced HIV infection and a substantial burden of AIDS-defining illnesses may represent an expected consequence of delayed presentation and increased antigen load. However, the single-center, retrospective design and the limited sample size restrict the generalizability of these findings. Therefore, prospective multicenter studies are needed to more clearly define early markers that may predict the development of IRIS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number:\u003c/strong\u003e not applicable\u003c/p\u003e","manuscriptTitle":"IRIS and Mortality in Advanced HIV: Post-Pandemic Experience from a Single-Center Case Series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 16:22:42","doi":"10.21203/rs.3.rs-7742557/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"be606fd7-688b-4172-940a-a9ac4ad42c7c","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-04T09:41:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-10 16:22:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7742557","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7742557","identity":"rs-7742557","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}