PhotoBio-HIV: Effects of Vascular Photobiomodulation on Inflammatory and Immunological Biomarkers in People Living with HIV/AIDS – Study Protocol for a Randomized, Double-Blind, Placebo-Controlled Clinical Trial

PhotoBio-HIV: Effects of Vascular Photobiomodulation on Inflammatory and Immunological Biomarkers in People Living with HIV/AIDS – Study Protocol for a Randomized, Double-Blind, Placebo-Controlled Clinical Trial | 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 Study protocol PhotoBio-HIV: Effects of Vascular Photobiomodulation on Inflammatory and Immunological Biomarkers in People Living with HIV/AIDS – Study Protocol for a Randomized, Double-Blind, Placebo-Controlled Clinical Trial Jean Fernando Sandeski Zuber, Erildo Vicente Muller, Francisco José Cidral Filho, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8880398/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract People living with HIV/AIDS (PLWHA), even when on stable antiretroviral therapy (ART), often experience premature aging and comorbidities associated with chronic, low-grade systemic inflammation. Conventional pharmacological strategies have limited effects in modulating this inflammatory state, highlighting the need for safe, accessible, and effective complementary therapies. Photobiomodulation (PBM), a noninvasive technique that uses low-intensity light to influence cellular activity and physiological processes, has shown promising results in modulating inflammation and improving vascular and immune function; however, its effects in PLWHA remain underexplored. This single-center, randomized, double-blind, placebo-controlled clinical trial will include 105 participants with HIV/AIDS on stable ART, allocated into three groups. The intervention will consist of PBM applied over the radial artery for 10 minutes, twice weekly for 4 weeks, with the protocol repeated at months 1, 3, and 5. Blood samples will be collected at seven time points to assess inflammatory, immunological, and coagulation biomarkers, as well as hematological parameters. If effective, vascular PBM may help reduce systemic inflammation and support its use in broader clinical settings. Clinical trial registration: Brazilian Clinical Trials Registry (ReBEC), identifier RBR-3mcg82f; Universal Trial Number (UTN) U1111-1312-7930; registered on December 5, 2024. Photobiomodulation Therapy HIV Inflammation Biomarkers Randomized Controlled Trial Antiretroviral Therapy Figures Figure 1 Figure 2 INTRODUCTION In recent decades, HIV infection has been widely managed as a chronic and controllable condition, mainly due to advances in antiretroviral therapy (ART), which has resulted in fewer side effects and a greater ability to suppress viral load more rapidly [ 1 , 2 ]. Despite these undeniable benefits, specific challenges remain. Among them, premature aging in people living with HIV (PLHIV) stands out, often accompanied by conditions more common in older age groups, which may occur up to 16 years earlier than in the population without HIV [ 3 ]. Although ART has contributed to increased life expectancy in PLHIV, these individuals are not exempt from the high risk of multimorbidity, such as metabolic, cardiovascular, oncologic, bone, and neurodegenerative disorders [ 4 , 5 , 6 ]. These conditions arise from a complex combination of factors, including chronic HIV infection itself, immunosenescence, a persistent inflammatory state, long-term ART use, chronic viral coinfections, and lifestyle-related factors [ 1 , 7 , 8 ]. In this context, low-level laser therapy as an adjunct to conventional treatment may be a supportive method for controlling inflammation, because when it interacts with the body, photobiomodulation (PBM) triggers a photobiological response capable of modifying several physiological processes. Key effects include modulation of the inflammatory response, increased adenosine triphosphate production, nitric oxide release, generation of reactive oxygen species, and effects on the function of sodium–potassium pumps and calcium channels in cell membranes [ 9 , 11 , 12 ]. Given this biological rationale and the evidence gap in PLHIV, it is pertinent to investigate transdermal vascular PBM as a complementary intervention to ART. METHODS This research was approved by the Ethics Committee in Research of the State University of Ponta Grossa (UEPG), Ponta Grossa, PR, Brazil (CAAE: 80485224.7.0000.0105; approval number: 7.185.040). The protocol was registered in the Brazilian Registry of Clinical Trials (ReBEC) under RBR-3mcg82f (registered on December 5, 2024) and assigned the Universal Trial Number (UTN) U1111-1312-7930. The trial registration record (WHO Trial Registration Data Set) is available at: https://ensaiosclinicos.gov.br/rg/RBR-3mcg82f and https://trialsearch.who.int/Trial2.aspx?TrialID=RBR-3mcg82f . Intervention PBM will be applied over the radial artery. Sessions will last 10 minutes, twice weekly for four weeks, and will be repeated in three cycles (months 1, 3, and 5), totaling 24 sessions over six months (Table 1 ). Blood samples will be collected at seven time points: before and after each PBM cycle and at the final endpoint at 180 days, as shown in Fig. 1 . Table 1 Technical parameters and intervention schedule by study group Group Laser Color Wavelength (nm) Power (mW) Emission Mode Time per Session Energy per Session (J) Frequency Total sessions Total duration Red Group Red 637 300 Pulsed 10 minutes 180 Twice a week in monthly cycles 24 6 months Violet Group Violet 405 300 Pulsed 10 minutes 180 Twice a week in monthly cycles 24 6 months Gray Group Simulated (Placebo) — — Without light emission 10 minutes 0 Twice a week in monthly cycles 24 6 months Laboratory samples and tests Samples will be labeled, batch-stored, and frozen at − 80°C, then sent to the supporting laboratory for analysis of IL-1β, IL-6, IL-10, TNF-α, D-dimer, high-sensitivity C-reactive protein (hs-CRP), nitric oxide, CD4 + T-cell count, viral load, and hematological parameters assessed by complete blood count (CBC). Sample size Sample size was estimated using G*Power software (version 3.1.9.2), based on Pereira et al. [ 31 ], using analysis of variance (ANOVA). A sample of 105 participants (35 per group) was defined, considering a significance level of p < 0.05, 80% statistical power, a 95% confidence interval, and an effect size of 0.25. Recruitment Eligible individuals will be identified through systematic screening of electronic medical records and referral by the multidisciplinary team. Spontaneous expressions of interest at the SAE/CTA will also be considered, provided eligibility criteria are met. Sequence generation The allocation sequence will be generated using the blockrand package in R software, with block randomization and a 1:1:1 ratio for the Red Group, Violet Group, and Gray Group (placebo simulation). Eligible participants will receive sequential identification according to the order of inclusion (Fig. 2 ). Allocation concealment will be ensured through sequentially numbered codes managed by a member of the support team who does not participate in clinical assessment or data analysis. Allocation will be disclosed only on the first day of the intervention and only to the support team responsible for administering PBM. Blinding and unblinding The study will keep participants and investigators responsible for clinical assessments and data analysis blinded to group allocation, with access to the allocation list restricted to the support team that will deliver the intervention. To ensure blinding, the PBM devices will be identical, and all participants will wear opaque goggles during sessions to prevent visual identification of light emission. Unblinding will be permitted only in exceptional situations, when necessary to ensure participant safety or to manage a serious adverse event. Statistical analysis Quantitative variables will be summarized as mean (SD) or median (IQR), and categorical variables as frequencies and proportions. Normality will be assessed with the Shapiro–Wilk test. Group comparisons will use t test/ANOVA for normally distributed data and Mann–Whitney/Kruskal–Wallis otherwise. Biomarker associations with treatment response will be evaluated using Pearson or Spearman correlation, as appropriate. Longitudinal changes will be analyzed using linear mixed-effects models, with multiple-comparison adjustments applied when necessary. Analyses will be performed in R. Discussion Systemic inflammation in PLWHA has been identified as a central factor in CD4 + T-cell depletion and in the immune dysfunction associated with HIV disease progression [ 13 , 14 ]. Even with ART and viral suppression, infection sustains a low-grade inflammatory state and chronic immune activation, which contribute to progressive biological deterioration and the early onset of immunosenescence [ 14 , 15 ]. This dysfunction is related to processes such as hypercoagulability, fibrosis, and tissue damage, which over time favor non–AIDS-related comorbidities that are more frequent than in the general population [ 8 , 16 ]. Persistent viral replication, intermittent low-level viremia (viral blips), secondary coinfections, and gut dysbiosis with microbial translocation have also been described as factors that maintain this scenario, keeping the immune system in a continuous state of alert [ 17 – 19 ]. Levels of inflammatory cytokines in PLWHA across the course of infection resemble those observed in uninfected individuals who are 4 to 12 years older, which aligns with the earlier development of multimorbidity [ 4 , 20 ]. This sustained antigenic stimulation is reflected in increased inflammatory biomarkers such as IL-1β, IL-4, IL-6, IL-10, IFN-γ, TNF-α, hs-CRP, and D-dimer, forming an inflammatory profile [ 21 , 18 , 22 , 23 ]. In addition to indicating persistent immune activation, these markers have prognostic relevance, as plasma levels of IL-6, IL-10, hs-CRP, D-dimer, and sCD14 act as independent predictors of morbidity and mortality [ 13 , 24 , 25 ]. Thus, a sustained inflammatory profile reinforces the role of ongoing immune activation in accelerating immunosenescence and in the occurrence of multimorbidity [ 24 , 26 ]. In this context, PBM is presented as an adjunct therapy used since the 1960s for pain relief, wound healing, and inflammation control, with effects that include immune modulation, antibacterial action, anti-inflammatory properties, and vasodilation [ 9 , 27 , 28 ]. It is a technique that uses low-intensity electromagnetic radiation emitted by laser or LED, generally in the red and near-infrared (600–1100 nm) and violet (405 nm) spectra [ 29 , 30 ]. Absorption by intracellular chromophores—particularly cytochrome c oxidase—triggers reactions such as increased ATP production, modulation of nitric oxide, and regulation of reactive oxygen species [ 9 , 12 ]. At the physiological level, improvements in mitochondrial function, vasodilation, increased perfusion, and regulation of the inflammatory response have been described, including effects on gene expression of pro- and anti-inflammatory cytokines [ 30 ], with potential influence on interleukins and TNF-α in human peripheral blood mononuclear cells [ 10 ]. Recent evidence also indicates improvements in blood rheological properties and tissue oxygenation [ 11 , 31 ]. Despite advances in ART, few complementary strategies directly target the mechanisms underlying persistent chronic inflammation in PLWHA [ 32 ]. Transdermal vascular PBM emerges as a promising alternative; however, a relevant gap remains in the literature regarding its application in PLWHA and its effects on inflammatory, immunological, and coagulation biomarkers, supporting the relevance and originality of this protocol. Future validation through multicenter and longer-duration studies is needed to assess the durability and generalizability of the findings. Conclusion If the effects of PBM reported in the literature are confirmed in the target population, this strategy may be established as a noninvasive, low-risk, and scalable approach, expanding care options for persistent inflammation in HIV management. Declarations Funding: This study received partial funding through Public Call 23/2024 – Institutional Universal Research Program (Basic and Applied), from Fundação Araucária for the Support of Scientific and Technological Development of Paraná (Protocol No. PBA2025201000167). The funds were approved exclusively to cover laboratory test costs. The funding agency had no role in the study design, in writing the protocol, or in the decision to submit the manuscript for publication. Competing interests: The authors declare that they have no competing interests. Ethics approval: Ethics approval was granted by the Ethics Committee in Research of the State University of Ponta Grossa (UEPG), Ponta Grossa, PR, Brazil (CAAE: 80485224.7.0000.0105; approval number: 7.185.040). The trial was registered in the Brazilian Registry of Clinical Trials (ReBEC) under RBR-3mcg82f and assigned the Universal Trial Number (UTN) U1111-1312-7930. Consent to participate: Written informed consent will be obtained from all participants before enrollment. Consent for publication: Not applicable. Availability of data and materials: Not applicable. No datasets were generated or analyzed in this study protocol. Code availability: This study will use R software for sequence generation and statistical analyses (including the blockrand package for randomization). The scripts used for randomization, data processing, and statistical analyses will be made available by the corresponding author upon reasonable request. Authors’ contributions: All authors contributed to the study conception and design. Jean Fernando Sandeski Zuber will be responsible for logistics, recruitment, training, and operational implementation of the intervention. Pollyanna Kassia de Oliveira Borges will contribute to field practice and methodology. Camila Marinelli Martins will contribute mainly to methodology and statistical planning/analysis. Manoelito Ferreira Silva Junior will be responsible for laboratory interpretation of results. Daniel Fernandes Martins, Erildo Vicente Muller, and Francisco José Cidral Filho will contribute to study supervision and manuscript review. All authors read and approved the final manuscript. Author Contribution All authors contributed to the study conception and design. Jean Fernando Sandeski Zuber will be responsible for logistics, recruitment, training, and operational implementation of the intervention. Pollyanna Kassia de Oliveira Borges will contribute to field practice and methodology. Camila Marinelli Martins will contribute mainly to methodology and statistical planning/analysis. Manoelito Ferreira Silva Junior will be responsible for laboratory interpretation of results. Daniel Fernandes Martins, Erildo Vicente Muller, and Francisco José Cidral Filho will contribute to study supervision and manuscript review. All authors read and approved the final manuscript. Data Availability Not applicable. No datasets were generated or analyzed in this study protocol. References Trickey A, Sabin CA, Burkholder G, Crane H, d'Arminio Monforte A, Egger M, et al. 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Hoenigl M, Kessler HH, Gianella S. Editorial: HIV-Associated Immune Activation and Persistent Inflammation. Front Immunol. 2019;10:2858. https://doi.org/10.3389/fimmu.2019.02858 . Lin YP, Ding RS, Ding CH, Yin YS, Chen YS, Chen JS, et al. Effects of intravascular photobiomodulation on insomnia, muscle soreness, and biochemistry profiles: an eight-year retrospective cohort. Med (Kaunas). 2023;59(6):1006. https://doi.org/10.3390/medicina59061006 . Mester E, Szende B, Gärtner P. Die Wirkung der Lasstrahlen auf den Haarwuchs der Maus [The effect of laser beams on the growth of hair in mice]. Radiobiol Radiother (Berl). 1968;9(5):621–6. Felician MCP, Belotto R, Tardivo JP, Baptista MS, Martins WK. Photobiomodulation: Cellular, molecular, and clinical aspects. J Photochem Photobiology. 2023;17:100197. https://doi.org/10.1016/j.jpap.2023.100197 . Serrage H, Heiskanen V, Palin WM, Cooper PR, Milward MR, Hadis M, et al. 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Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 09 Apr, 2026 Reviews received at journal 24 Mar, 2026 Reviewers agreed at journal 05 Mar, 2026 Reviewers agreed at journal 03 Mar, 2026 Reviewers invited by journal 02 Mar, 2026 Editor assigned by journal 27 Feb, 2026 Submission checks completed at journal 26 Feb, 2026 First submitted to journal 14 Feb, 2026 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-8880398","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":600597151,"identity":"b008307a-d774-4ac7-8431-14c46ac383e8","order_by":0,"name":"Jean Fernando Sandeski 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2","display":"","copyAsset":false,"role":"figure","size":397716,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart illustrating participant recruitment, eligibility assessment, randomization into research groups, intervention, and data analysis\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-8880398/v1/0e3e32e8dd56233e1b4e3054.png"},{"id":104177630,"identity":"0eed3231-8dc7-4580-ab67-1f76b29c7311","added_by":"auto","created_at":"2026-03-08 16:49:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1364774,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8880398/v1/40870e4e-8a0f-4fc5-a15a-a0e0b0cba8ba.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"PhotoBio-HIV: Effects of Vascular Photobiomodulation on Inflammatory and Immunological Biomarkers in People Living with HIV/AIDS – Study Protocol for a Randomized, Double-Blind, Placebo-Controlled Clinical Trial","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eIn recent decades, HIV infection has been widely managed as a chronic and controllable condition, mainly due to advances in antiretroviral therapy (ART), which has resulted in fewer side effects and a greater ability to suppress viral load more rapidly [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Despite these undeniable benefits, specific challenges remain. Among them, premature aging in people living with HIV (PLHIV) stands out, often accompanied by conditions more common in older age groups, which may occur up to 16 years earlier than in the population without HIV [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough ART has contributed to increased life expectancy in PLHIV, these individuals are not exempt from the high risk of multimorbidity, such as metabolic, cardiovascular, oncologic, bone, and neurodegenerative disorders [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These conditions arise from a complex combination of factors, including chronic HIV infection itself, immunosenescence, a persistent inflammatory state, long-term ART use, chronic viral coinfections, and lifestyle-related factors [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this context, low-level laser therapy as an adjunct to conventional treatment may be a supportive method for controlling inflammation, because when it interacts with the body, photobiomodulation (PBM) triggers a photobiological response capable of modifying several physiological processes. Key effects include modulation of the inflammatory response, increased adenosine triphosphate production, nitric oxide release, generation of reactive oxygen species, and effects on the function of sodium\u0026ndash;potassium pumps and calcium channels in cell membranes [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Given this biological rationale and the evidence gap in PLHIV, it is pertinent to investigate transdermal vascular PBM as a complementary intervention to ART.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis research was approved by the Ethics Committee in Research of the State University of Ponta Grossa (UEPG), Ponta Grossa, PR, Brazil (CAAE: 80485224.7.0000.0105; approval number: 7.185.040). The protocol was registered in the Brazilian Registry of Clinical Trials (ReBEC) under RBR-3mcg82f (registered on December 5, 2024) and assigned the Universal Trial Number (UTN) U1111-1312-7930. The trial registration record (WHO Trial Registration Data Set) is available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ensaiosclinicos.gov.br/rg/RBR-3mcg82f\u003c/span\u003e\u003cspan address=\"https://ensaiosclinicos.gov.br/rg/RBR-3mcg82f\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e and \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://trialsearch.who.int/Trial2.aspx?TrialID=RBR-3mcg82f\u003c/span\u003e\u003cspan address=\"https://trialsearch.who.int/Trial2.aspx?TrialID=RBR-3mcg82f\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eIntervention\u003c/h2\u003e \u003cp\u003ePBM will be applied over the radial artery. Sessions will last 10 minutes, twice weekly for four weeks, and will be repeated in three cycles (months 1, 3, and 5), totaling 24 sessions over six months (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Blood samples will be collected at seven time points: before and after each PBM cycle and at the final endpoint at 180 days, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" 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\u003eTechnical parameters and intervention schedule by study group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLaser Color\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWavelength (nm)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePower (mW)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEmission Mode\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTime per Session\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEnergy per Session (J)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFrequency\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTotal sessions\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eTotal duration\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRed Group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e637\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePulsed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10 minutes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTwice a week in monthly cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eViolet Group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eViolet\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e405\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePulsed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10 minutes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTwice a week in monthly cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGray Group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSimulated (Placebo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWithout light emission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10 minutes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTwice a week in monthly cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLaboratory samples and tests\u003c/h3\u003e\n\u003cp\u003eSamples will be labeled, batch-stored, and frozen at \u0026minus;\u0026thinsp;80\u0026deg;C, then sent to the supporting laboratory for analysis of IL-1β, IL-6, IL-10, TNF-α, D-dimer, high-sensitivity C-reactive protein (hs-CRP), nitric oxide, CD4\u0026thinsp;+\u0026thinsp;T-cell count, viral load, and hematological parameters assessed by complete blood count (CBC).\u003c/p\u003e\n\u003ch3\u003eSample size\u003c/h3\u003e\n\u003cp\u003eSample size was estimated using G*Power software (version 3.1.9.2), based on Pereira et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], using analysis of variance (ANOVA). A sample of 105 participants (35 per group) was defined, considering a significance level of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, 80% statistical power, a 95% confidence interval, and an effect size of 0.25.\u003c/p\u003e\n\u003ch3\u003eRecruitment\u003c/h3\u003e\n\u003cp\u003eEligible individuals will be identified through systematic screening of electronic medical records and referral by the multidisciplinary team. Spontaneous expressions of interest at the SAE/CTA will also be \u003cem\u003econsidered, provided eligibility criteria are met.\u003c/em\u003e\u003c/p\u003e\n\u003ch3\u003eSequence generation\u003c/h3\u003e\n\u003cp\u003eThe allocation sequence will be generated using the blockrand package in R software, with block randomization and a 1:1:1 ratio for the Red Group, Violet Group, and Gray Group (placebo simulation). Eligible participants will receive sequential identification according to the order of inclusion (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Allocation concealment will be ensured through sequentially numbered codes managed by a member of the support team who does not participate in clinical assessment or data analysis. Allocation will be disclosed only on the first day of the intervention and only to the support team responsible for administering PBM.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBlinding and unblinding\u003c/h2\u003e \u003cp\u003eThe study will keep participants and investigators responsible for clinical assessments and data analysis blinded to group allocation, with access to the allocation list restricted to the support team that will deliver the intervention. To ensure blinding, the PBM devices will be identical, and all participants will wear opaque goggles during sessions to prevent visual identification of light emission. Unblinding will be permitted only in exceptional situations, when necessary to ensure participant safety or to manage a serious adverse event.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eQuantitative variables will be summarized as mean (SD) or median (IQR), and categorical variables as frequencies and proportions. Normality will be assessed with the Shapiro\u0026ndash;Wilk test. Group comparisons will use t test/ANOVA for normally distributed data and Mann\u0026ndash;Whitney/Kruskal\u0026ndash;Wallis otherwise. Biomarker associations with treatment response will be evaluated using Pearson or Spearman correlation, as appropriate. Longitudinal changes will be analyzed using linear mixed-effects models, with multiple-comparison adjustments applied when necessary. Analyses will be performed in R.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSystemic inflammation in PLWHA has been identified as a central factor in CD4\u0026thinsp;+\u0026thinsp;T-cell depletion and in the immune dysfunction associated with HIV disease progression [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Even with ART and viral suppression, infection sustains a low-grade inflammatory state and chronic immune activation, which contribute to progressive biological deterioration and the early onset of immunosenescence [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. This dysfunction is related to processes such as hypercoagulability, fibrosis, and tissue damage, which over time favor non\u0026ndash;AIDS-related comorbidities that are more frequent than in the general population [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Persistent viral replication, intermittent low-level viremia (viral blips), secondary coinfections, and gut dysbiosis with microbial translocation have also been described as factors that maintain this scenario, keeping the immune system in a continuous state of alert [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLevels of inflammatory cytokines in PLWHA across the course of infection resemble those observed in uninfected individuals who are 4 to 12 years older, which aligns with the earlier development of multimorbidity [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This sustained antigenic stimulation is reflected in increased inflammatory biomarkers such as IL-1β, IL-4, IL-6, IL-10, IFN-γ, TNF-α, hs-CRP, and D-dimer, forming an inflammatory profile [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In addition to indicating persistent immune activation, these markers have prognostic relevance, as plasma levels of IL-6, IL-10, hs-CRP, D-dimer, and sCD14 act as independent predictors of morbidity and mortality [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Thus, a sustained inflammatory profile reinforces the role of ongoing immune activation in accelerating immunosenescence and in the occurrence of multimorbidity [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this context, PBM is presented as an adjunct therapy used since the 1960s for pain relief, wound healing, and inflammation control, with effects that include immune modulation, antibacterial action, anti-inflammatory properties, and vasodilation [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. It is a technique that uses low-intensity electromagnetic radiation emitted by laser or LED, generally in the red and near-infrared (600\u0026ndash;1100 nm) and violet (405 nm) spectra [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Absorption by intracellular chromophores\u0026mdash;particularly cytochrome c oxidase\u0026mdash;triggers reactions such as increased ATP production, modulation of nitric oxide, and regulation of reactive oxygen species [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. At the physiological level, improvements in mitochondrial function, vasodilation, increased perfusion, and regulation of the inflammatory response have been described, including effects on gene expression of pro- and anti-inflammatory cytokines [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], with potential influence on interleukins and TNF-α in human peripheral blood mononuclear cells [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Recent evidence also indicates improvements in blood rheological properties and tissue oxygenation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite advances in ART, few complementary strategies directly target the mechanisms underlying persistent chronic inflammation in PLWHA [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Transdermal vascular PBM emerges as a promising alternative; however, a relevant gap remains in the literature regarding its application in PLWHA and its effects on inflammatory, immunological, and coagulation biomarkers, supporting the relevance and originality of this protocol. Future validation through multicenter and longer-duration studies is needed to assess the durability and generalizability of the findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIf the effects of PBM reported in the literature are confirmed in the target population, this strategy may be established as a noninvasive, low-risk, and scalable approach, expanding care options for persistent inflammation in HIV management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis study received partial funding through Public Call 23/2024 \u0026ndash; Institutional Universal Research Program (Basic and Applied), from Funda\u0026ccedil;\u0026atilde;o Arauc\u0026aacute;ria for the Support of Scientific and Technological Development of Paran\u0026aacute; (Protocol No. PBA2025201000167). The funds were approved exclusively to cover laboratory test costs. The funding agency had no role in the study design, in writing the protocol, or in the decision to submit the manuscript for publication.\u003c/p\u003e \u003cp\u003eCompeting interests: The authors declare that they have no competing interests.\u003c/p\u003e \u003cp\u003eEthics approval: Ethics approval was granted by the Ethics Committee in Research of the State University of Ponta Grossa (UEPG), Ponta Grossa, PR, Brazil (CAAE: 80485224.7.0000.0105; approval number: 7.185.040). The trial was registered in the Brazilian Registry of Clinical Trials (ReBEC) under RBR-3mcg82f and assigned the Universal Trial Number (UTN) U1111-1312-7930.\u003c/p\u003e \u003cp\u003eConsent to participate: Written informed consent will be obtained from all participants before enrollment.\u003c/p\u003e \u003cp\u003eConsent for publication: Not applicable.\u003c/p\u003e \u003cp\u003eAvailability of data and materials: Not applicable. No datasets were generated or analyzed in this study protocol.\u003c/p\u003e \u003cp\u003eCode availability: This study will use R software for sequence generation and statistical analyses (including the blockrand package for randomization). The scripts used for randomization, data processing, and statistical analyses will be made available by the corresponding author upon reasonable request.\u003c/p\u003e \u003cp\u003eAuthors\u0026rsquo; contributions: All authors contributed to the study conception and design. Jean Fernando Sandeski Zuber will be responsible for logistics, recruitment, training, and operational implementation of the intervention. Pollyanna Kassia de Oliveira Borges will contribute to field practice and methodology. Camila Marinelli Martins will contribute mainly to methodology and statistical planning/analysis. Manoelito Ferreira Silva Junior will be responsible for laboratory interpretation of results. Daniel Fernandes Martins, Erildo Vicente Muller, and Francisco Jos\u0026eacute; Cidral Filho will contribute to study supervision and manuscript review. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. Jean Fernando Sandeski Zuber will be responsible for logistics, recruitment, training, and operational implementation of the intervention. Pollyanna Kassia de Oliveira Borges will contribute to field practice and methodology. Camila Marinelli Martins will contribute mainly to methodology and statistical planning/analysis. Manoelito Ferreira Silva Junior will be responsible for laboratory interpretation of results. Daniel Fernandes Martins, Erildo Vicente Muller, and Francisco Jos\u0026eacute; Cidral Filho will contribute to study supervision and manuscript review. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eNot applicable. No datasets were generated or analyzed in this study protocol.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTrickey A, Sabin CA, Burkholder G, Crane H, d'Arminio Monforte A, Egger M, et al. Life expectancy after 2015 of adults with HIV on long-term antiretroviral therapy in Europe and North America: a collaborative analysis of cohort studies. Lancet HIV. 2023;10(5):e295\u0026ndash;307. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S2352-3018(23)00028-0\u003c/span\u003e\u003cspan address=\"10.1016/S2352-3018(23)00028-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGutierrez MDM, Mateo MG, Vidal F, Domingo P. 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Biomed Res Int. 2016;2016:3420638. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1155/2016/3420638\u003c/span\u003e\u003cspan address=\"10.1155/2016/3420638\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Photobiomodulation Therapy, HIV, Inflammation, Biomarkers, Randomized Controlled Trial, Antiretroviral Therapy","lastPublishedDoi":"10.21203/rs.3.rs-8880398/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8880398/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePeople living with HIV/AIDS (PLWHA), even when on stable antiretroviral therapy (ART), often experience premature aging and comorbidities associated with chronic, low-grade systemic inflammation. Conventional pharmacological strategies have limited effects in modulating this inflammatory state, highlighting the need for safe, accessible, and effective complementary therapies. Photobiomodulation (PBM), a noninvasive technique that uses low-intensity light to influence cellular activity and physiological processes, has shown promising results in modulating inflammation and improving vascular and immune function; however, its effects in PLWHA remain underexplored. This single-center, randomized, double-blind, placebo-controlled clinical trial will include 105 participants with HIV/AIDS on stable ART, allocated into three groups. The intervention will consist of PBM applied over the radial artery for 10 minutes, twice weekly for 4 weeks, with the protocol repeated at months 1, 3, and 5. Blood samples will be collected at seven time points to assess inflammatory, immunological, and coagulation biomarkers, as well as hematological parameters. If effective, vascular PBM may help reduce systemic inflammation and support its use in broader clinical settings. 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