Clinical outcomes of Dolutegravir treatment in people living with HIV in Brazil: Protocol for the CODE Cohort

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With the recent global shift towards DTG as a preferred option for first-line ART, particularly in low- and middle-income countries, there is vital need for comprehensive real-world data to inform its widespread use. CODE aims to fill this knowledge gap by assessing the clinical outcomes of both ART-naïve and ART-experienced patients initiating DTG-based regimens, as well as those who have switched from non-DTG-based ART. The primary objective of this study is to determine the proportion of patients who discontinue DTG due to any adverse events, specifically focusing on metabolic and psychiatric outcomes. Secondary objectives include evaluating the rates of virological suppression, the occurrence of immune reconstitution inflammatory syndrome (IRIS), changes in body mass index (BMI), and the development of HIV drug resistance. The CODE cohort will enroll approximately 5000 participants from multiple clinical sites across Brazil, including 2500 ART-naïve individuals, 1000 patients switching to DTG-based regimens for various reasons, and a comparator group of 1500 individuals who initiated non-DTG-based ART between 2013 and 2016, before DTG was available in the country. Participants will be followed for up to 36 months, with data collection points at baseline, 6, 12, 24, and 36 months. This study is expected to generate critical insights into the long-term outcomes associated with DTG-based ART, particularly in real-world settings that reflect the complexities of routine clinical care. By providing robust data on the effectiveness and safety of DTG in a diverse patient population, the CODE study aims to contribute to the optimization of HIV treatment strategies both in Brazil and globally. Figures Figure 1 Figure 2 INTRODUCTION The rapid expansion of access to antiretroviral therapy (ART) in low- and middle-income countries has been a significant milestone in the global fight against HIV. In Brazil, where ART has been universally available since 1996, the recent introduction of Dolutegravir (DTG)-based regimens as first-line therapy represents a critical advancement. The World Health Organization (WHO) guidelines now recommend DTG, combined with two nucleoside reverse transcriptase inhibitors (NRTIs) such as tenofovir and lamivudine, as the preferred regimen for initiating ART. ( 1 – 3 ) However, despite the advantages of DTG, including its virologic potency, high barrier to resistance, and favorable tolerability profile, there remain critical gaps in understanding its long-term outcomes, particularly in real-world settings. The CODE cohort study is designed to address these gaps by providing robust data on the clinical outcomes of DTG-based ART in a large cohort of people living with HIV in Brazil. This multicenter, prospective observational study will follow ART-naïve patients starting DTG-based regimens, those switching to DTG due to virological failure, and a comparator group of patients who initiated non-DTG-based ART before DTG was introduced in Brazil. Several specific concerns have emerged from recent studies that highlight the need for further investigation. For example, the rapid virologic suppression associated with integrase inhibitors (INIs) like DTG has been linked to an increased risk of immune reconstitution inflammatory syndrome (IRIS), particularly among patients with low CD4 cell counts at ART initiation, although other reports showed no difference in comparison with regimens based in other antiretroviral drugs. In European cohorts, INI-based regimens have been associated with a 2–3 fold increase in IRIS risk among patients with CD4 counts below 200 cells/mm³. Moreover, observational studies have pointed to variable rates of DTG discontinuation due to central nervous system (CNS) and metabolic toxicities.( 4 – 10 ) Given these potential risks, there is an urgent need to understand the broader implications of DTG use, especially as it becomes more widely available in settings with a high burden of late-stage HIV and co-infections like tuberculosis. The Brazilian context offers a unique opportunity to study these issues. With a large and diverse population of people living with HIV, Brazil's healthcare system provides a natural laboratory for evaluating the real-life effectiveness and safety of DTG-based regimens. The CODE study aims to quantify the frequency of DTG discontinuation due to adverse events, evaluate virological suppression rates, assess clinical outcomes such as IRIS, weight gain, and CNS effects, and identify the development of drug resistance in patients on DTG-based therapy. This study will follow a cohort of 5000 participants over 36 months, including 2500 ART-naïve individuals, 1000 ART patients switching to DTG for various reasons, and a retrospective cohort of 1500 individuals never took DTG. The broad inclusion criteria and diverse participant population will allow for a comprehensive assessment of DTG's impact across various stages of HIV infection and treatment histories. In summary, the CODE cohort study is poised to provide critical insights into the real-world outcomes of DTG-based ART in Brazil. By addressing the knowledge gaps related to DTG's safety and effectiveness, this study will contribute valuable evidence to guide treatment strategies in similar low- and middle-income country settings worldwide. MATERIALS AND METHODS Aim, Design, and Setting The CODE cohort study is a multicenter, prospective observational study designed to assess the clinical outcomes of people living with HIV who are initiating or switching to Dolutegravir (DTG)-based antiretroviral therapy (ART) in Brazil. The study is conducted across multiple clinical sites, including major HIV treatment centers in the cities of Rio de Janeiro, Salvador, São Paulo, and Porto Alegre. Additional sites include clinics and hospitals in Caxias do Sul, Ribeirão Preto, Vitoria, Nova Iguaçu, Campinas, São Caetano do Sul, Natal and Botucatu (See Fig. 1) Study Population and Sample Size The study aims to enroll a total of 5000 participants, distributed across four groups: Group 1 includes 2500 ART-naïve individuals starting a DTG-based regimen; Group 2 includes 500 patients on stable ART who switch to DTG-based regimens for any reason, and Group 3 includes 500 ART-experienced patients switching to DTG due to virological failure on their current regimen. The fourth Group ( 4 ) is a comparator group that includes data from 1500 patients who initiated non-DTG-based ART between 2013 and 2016 and have not switched to a DTG regimen. Participants will be followed for up to 36 months, with data collection points at baseline, 6, 12, 24, and 36 months. This large and diverse sample size is designed to ensure sufficient power to detect differences in clinical outcomes between the groups, particularly in terms of treatment discontinuation, virological suppression, and the incidence of adverse events. Inclusion and Exclusion Criteria Inclusion Criteria include: 1) documented HIV infection by plasma HIV RNA viral load, rapid HIV test, or any licensed ELISA test. If diagnosis was made by rapid or serological test a confirmation by an alternative method such as Western Blot, HIV culture, or HIV pro-viral DNA is required; 2) age ≥ 15 years; and 3) initiation of a DTG-based regimen or for the comparator Group 4, a non-DTG-based ART regimen between 2013 and 2016. In the three prospective groups, women of child-bearing potential must be willing to use effective contraceptive methods. Patients are excluded from the drug-naive Group 1 if they have previously used ART. Persons incarcerated or on compulsory detention for psychiatric or physical illness are excluded. Participant Selection and Recruitment Participants are being recruited from the clinical sites based on their eligibility and willingness to participate in the study. The selection process will ensure a heterogeneous population reflective of the broader HIV-positive population in Brazil. The broad inclusion criteria are designed to capture a wide range of patient characteristics, allowing for subgroup analyses and the identification of factors associated with specific outcomes. Study Procedures At baseline, all prospective participants will undergo comprehensive assessments, including: collection of demographic data (e.g., age, gender, education level); documentation of HIV infection status, including CD4 + and CD8 + cell counts, and HIV RNA levels. A detailed medical history, including prior ART use, co-infections, and other relevant health conditions and a physical examination that includes weight, height, abdominal circumference, and blood pressure is taken. Laboratory evaluations include complete blood count (CBC), liver and renal function tests, fasting glucose and lipid profile, and urinalysis for proteinuria and blood samples are collected for plasma storage to facilitate future resistance testing. Finally, a Quality-of-Life assessment using the WHO QoL BREF is conducted for those switching to DTG-based regimens. Participants will be followed at 6, 12, 24, and 36 months (Table 1 ). During these visits, the following will be monitored: continued documentation of ART regimen and any changes, including reasons for switching or discontinuation; clinical evaluations, including measurement of vital signs, weight, and assessment of any new symptoms or adverse events; repeat laboratory tests to monitor HIV RNA levels, CD4 + and CD8 + counts, markers of liver and renal function, and assessments of adherence to ART, and any concomitant medications. For those switching to DTG-based regimens, quality of life assessments are conducted at 6 and 12 months. Table 1 Schedule of assessments for prospective Groups 1, 2, and 3. Requirement *Baseline Follow-up visits 6 months 12 months 24 months 36 months Informed consent X Demographics, including education X Documentation of HIV infection X CD4 + cell count and CD4% / CD8 + cell count and CD8% X X*** X*** X*** X*** Targeted health history and clinical evaluation X X X X X Record of the highest CD4 + cell count (absolute and %) and HIV RNA documented in the medical record at any time in the past. X Findings from genotyping or other form of acceptable ART resistance testing, if available X X X X X Recording of selected concomitant medications (see item 3.5.1) X X X X X Pregnancy status X X X X X Quality of life assessment (switch group) X X X Use of alcohol and recreational drugs X X X X X Anthropometric measures** X X X X X Plasma Sample Storage X HIV RNA level X X X X X CBC: hemoglobin, hematocrit, white blood cell count (WBC) with differential and platelets X X X X X Renal function measurement: serum creatinine X X X X X Liver function measurements: ALT, AST, alkaline phosphatase, total bilirubin and albumin X X X X Glucose X X X X X Total cholesterol, LDL, HDL, triglycerides X X X X X Dipstick urinalysis for protein X X X X X DEXA and / or the assessment of body fat impedance (whenever possible) X X X X X *(< 60 days before participant´s study) ** Anthropometric measurements (weight, abdominal waist, hips and height (height only on visit 1). *** If possible. # 60 days before or after the scheduled date. Participants in Group 4 are identified from existing clinical databases and patient records across the participating sites. Eligible participants must have initiated non-DTG-based ART within the specified timeframe (2013–2016) and must have adequate medical records that allow for the extraction of relevant clinical data. Inclusion criteria focus on ensuring that participants have consistent follow-up data available over the study period, with particular attention to ART regimen details, clinical outcomes, and laboratory results. Baseline data is extracted for each participant from the time of ART initiation, and includes: demographic information, baseline CD4 count, HIV RNA levels, and any comorbid conditions present at the time of ART initiation (Table 2 ). Baseline data also include details of the initial ART regimen, reasons for selecting the non-DTG-based regimen, and any contraindications to DTG that may have influenced treatment decisions. Follow-up data collection for this group corresponds to the same intervals used for the prospective groups: at 6, 12, 24, and 36 months after ART initiation, and includes: virological, immunological, clinical outcomes, adverse events and treatment modifications (Table 2 ). Table 2 Schedule of assessments for Restropective Arm (Group 4) Requirement *Baseline Follow-up visits 6 months 12 months 24 months 36 months Informed consent X Demographics X Documentation of HIV infection X CD4 + cell count and CD4% / CD8 + cell count and CD8% X X*** X*** X*** X*** Targeted health history and clinical evaluation X X X X X Record of the highest CD4 + cell count (absolute and %) and HIV RNA documented in the medical record at any time in the past. X Findings from genotyping or other form of acceptable ART resistance testing, if available X X X X X Recording of selected concomitant medications (see item 3.5.1) X X X X X Pregnancy status X X X X X Use of alcohol and recreational drugs X X X X X Anthropometric measures** X X X X X HIV RNA level X X X X X CBC: hemoglobin, hematocrit, white blood cell count (WBC) with differential and platelets X X X X X Renal function measurement: serum creatinine X X X X X Liver function measurements: ALT, AST, alkaline phosphatase, total bilirubin and albumin X X X X X Glucose X X X X X Total cholesterol, LDL, HDL, triglycerides X X X X X Dipstick urinalysis for protein X X X X X *(< 60 days before participant´s study) ** Anthropometric measurements (weight, abdominal waist, hips and height (height only on visit 1). *** If possible. # 60 days before or after the scheduled date. Adverse events (AEs) and serious adverse events (SAEs) are recorded and reported according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (Version 2.1). All SAEs will be reported to the study sponsor (ViiV Healthcare) and Institutional Review Boards (IRBs) within 24 hours of awareness. Data Management Data will be collected and managed using the Research Electronic Data Capture (REDCap) system hosted at the University of New Mexico (UNM). REDCap is a secure, web-based application designed to support data capture for research studies, providing an interface for validated data entry, audit trails, and automated export procedures. The system includes encryption, password protection, and internal quality controls to ensure the accuracy and completeness of data. Each clinical site will be responsible for entering data into REDCap, with regular monitoring and quality checks conducted by the study’s Statistics and Data Coordinating Center (SDCC) at UNM. Statistical Analysis Primary Analysis: The primary outcome is the proportion of treatment-naïve participants (Group 1) who discontinue DTG-based ART due to any event within 12 months, compared to those who initiated non-DTG-based ART (Group 4). This will be analyzed using a modified multivariable Poisson model, adjusting for potential confounders such as age, gender, race, and baseline CD4 count. Secondary Analysis: Secondary outcomes include virological suppression rates, changes in body mass index (BMI), incidence of IRIS, and the development of drug resistance. These will be assessed using similar multivariable model, as well as linear mixed models for continuous outcomes such as BMI changes. Exploratory Analysis: Exploratory outcomes, such as the frequency of cardiovascular events, new-onset diabetes, and quality of life changes, will be analyzed descriptively and use appropriate statistical tests for between-group comparisons. Handling of Missing Data: Given the observational nature of the study, missing data is expected. The analysis will include strategies such as multiple imputation for missing data assumed to be missing at random (MAR) or completely at random (MCAR). Sensitivity analyses will be conducted to assess the impact of missing data on the study’s findings. Ethical Considerations The study is being conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines, and local regulatory requirements. Ethical approval has been obtained from the IRBs at each participating site, and all participants will provide written informed consent prior to enrollment. Confidentiality will be maintained using coded identifiers, and data will be stored in secure, access-controlled databases. The study also includes provisions for the protection of vulnerable populations, such as adolescents and women of child-bearing potential. Status And Timeline Of The Study Figure 2 presents a Consort Diagram of enrolled and followed patients, missed and pending visits, and number of withdrawals. As of September 1st, 2024, the CODE study has a total of 4,288 patients enrolled. Baseline data has been collected for 2,077 patients in Group 1, 508 in Group 2, 188 in Group 3, and 1,515 in Group 4. Six month visits have been completed for 67.3% (1398/2077), 91.5% (465/508), and 63.3% (119/188) patients in Groups 1, 2, and 3 respectively. Group 4 has completed 6 month data for 85.3% of 1515 patients enrolled. Data is also shown for the 12, 24, and 36 month visits. DISCUSSION The CODE cohort study provides a unique opportunity to investigate the real-world outcomes of DTG-based ART among people living with HIV in Brazil. As a large, multicenter prospective observational study, CODE is poised to generate valuable data on the efficacy and safety of DTG-based regimens, particularly in diverse populations that may be underrepresented in randomized controlled trials. We expect this study will yield critical insights into the long-term outcomes of DTG-based ART, including the rates of treatment discontinuation due to adverse events, virological suppression, and the development of drug resistance. The primary finding of interest—the proportion of ART-naïve patients who discontinue DTG-based regimens—will provide essential information on the tolerability of DTG in real-world settings. Secondary outcomes, such as the frequency of metabolic and psychiatric events, will help elucidate the broader safety profile of DTG. The inclusion of ART-experienced patients and a retrospective comparator cohort of individuals on non-DTG regimens enhances the study's relevance by enabling a comparison across different treatment histories and clinical contexts. This will allow us to identify specific subgroups who may be at higher risk for adverse outcomes or who might benefit the most from DTG-based therapy. While the study's observational design offers the advantage of capturing real-world data, it also presents certain limitations that must be acknowledged. First, the non-randomized nature of the study may introduce selection bias, as patients initiating DTG-based therapy may differ systematically from those on other regimens. We have attempted to mitigate this by using broad inclusion criteria and adjusting for potential confounders in our statistical analyses. However, residual confounding cannot be entirely ruled out. Another potential limitation is the reliance on clinical sites across different regions of Brazil, which may lead to variability in data collection practices and clinical management. To address this, we have implemented standardized protocols for data collection and adverse event monitoring, along with regular quality assurance checks conducted by the UNM SDCC. Missing data is an inherent challenge in any longitudinal study, particularly in a cohort as large and diverse as CODE. We have taken steps to minimize missing data through rigorous follow-up procedures and will use appropriate statistical techniques, such as multiple imputation, to handle any missing data that does occur. The historical control group, which is the study’s comparator group may introduce bias, due to potential differences in patient populations and data quality. However, Brazilian guidelines for HIV treatment limit creation of a different control group using a different contemporary regimen. Finally, the observational nature of the study limits our ability to establish causal relationships between DTG use and the outcomes of interest. While we can identify associations, further studies, including randomized controlled trials, may be needed to confirm these findings and explore underlying mechanisms. Future Research Directions The findings from the CODE cohort study are expected to inform future research and clinical practice in several important ways. First, they will provide much-needed data on the safety and effectiveness of DTG in diverse populations, including those with late-stage HIV or co-infections such as tuberculosis and viral hepatitis. This is particularly relevant for low- and middle-income countries, where such data are often lacking. Second, the study's focus on real-world outcomes, such as treatment discontinuation and the development of drug resistance, will contribute to a better understanding of the long-term implications of DTG use in routine clinical practice. This could lead to the refinement of treatment guidelines and the development of strategies to optimize the use of DTG in different patient populations. In addition to the immediate findings, the CODE study will create a valuable biorepository of plasma samples that can be used for future research on HIV drug resistance and other virological and immunological outcomes. This resource will facilitate ongoing investigations into the mechanisms of DTG resistance and the identification of biomarkers for adverse outcomes. Dissemination and Impact The results of the CODE cohort study will be disseminated through peer-reviewed publications, conference presentations, and reports to national and international health agencies. We aim to share our findings with a wide audience, including clinicians, researchers, policymakers, and community stakeholders, to maximize the study's impact on HIV treatment and care. Given the global shift towards DTG-based regimens, particularly in resource-limited settings, the findings from CODE are expected to have significant implications for the management of HIV worldwide. By providing robust, real-world data on the safety and effectiveness of DTG, the study will contribute to the evidence base needed to guide treatment decisions and improve patient outcomes. In conclusion, the CODE cohort study represents a critical step forward in our understanding of DTG-based ART in diverse and often underrepresented populations. While the study has certain limitations, its strengths lie in its large, multicenter design, comprehensive data collection, and focus on real-world outcomes. The knowledge gained from this study will be invaluable in shaping the future of HIV treatment in Brazil and beyond. Declarations Ethics approval and consent to participate Ethical approval has been obtained from the IRBs at each participating site, and all participants will provide written informed consent prior to enrollment. Consent for publication Not aplicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests CB: Research grants: CNPq, GSK, Pfizer, Janssen. All but CNPq grants were awarded to Fundação Bahiana de Infectologia; Speaker and Advisory board (Gilead, GSK, MSD); SCW: Advisory Boar (ViiV); VM: Speaker (GSK, Gilead, Janssen); ANB: Speaker (Abbvie, Amgen-Bergamo, Astrazeneca, Boehringer Ingelheim, Celltrion, Dr. Reedys, Eurofarma, Gilead, GSK-ViiV, Janssen, Knigth Therapeutics, Moderna, MSD, Pfizer, Procter Gamble, Roche, Sanofi Pasteur, S. C. Johnson Johnson, Takeda, e Wyeth); KP: Has received research grants from the U.S. National Institutes of Health, and U.S. Centers for Disease Control and Prevention. All grants were awarded to the University of New Mexico. RZ: GSK employee; BJ: ViiV Healthcare employee. Funding The study was funded by a grant from ViiV Healthcare/GSK Brazil (GSK-212964) received by Fundação Bahiana de Infectologia Author contributions: CB and KP conceptualized the study and study design. CB, KP, CM-K, JE, MC, AA, and BC developed the data collection methods, and analytic approach. All Brazilian authors (CB, EL, CS, FB, MVGL, AR,SW, VM, TR, AN, RDS, MBB, TN, KM, MP, FL, ES) are involved in data collection. The manuscript was written by KP, CB and CM-K, and all other authors reviewed and provided input and editing to the writing. Acknowledgements Acknowledgements: We acknowledge the following individuals who contributed expertise and assistance for the study: Benjamin Chase for early data management assistance, and Mariana Herring for expert translation and communication services. Supporting information: Strobe checklist References Ministerio de Saude B. Protocolo Clínico e Diretrizes Terapêuticas para Manejo da Infecção pelo HIV em Adultos, 2024 [Internet]. 2024. Available from: https://bvsms.saude.gov.br/bvs/publicacoes/ pcdt_manejo_hiv_adultos_modulo1.pdf. Accessed in September, 06, 2024 World Health Organization. WHO recommends dolutegravir as preferred HIV treatment option in all populations [Internet]. 2023. Available from: https://www.who.int/news/item/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-option-in-all-populations.Accessed. Accessed September 06, 2024. Aprilianti S, Utami AM, Suwantika AA, Zakiyah N, Azis VI. The cost-effectiveness of dolutegravir in combination with tenofovir and lamivudine for HIV therapy: A systematic review. Clinicoecon Outcomes Res. 2024 Jan 26;16:25–34. Wijting I, Wit F, Rokx C. ATHENA national observational HIV cohort. ATHENA national observational HIV cohort. Gaillet A, Calin R, Flandre P, Tubiana R, Valantin M-A, Caumes E, et al. Increased risk of IRIS-associated tuberculosis in HIV-infected patients receiving Integrase Inhibitors. Infect Dis Now. 2021 Feb;51(1):90–3. Chan CK, Huang SS, Wong KH, Leung CC, Lee MP, Tsang TY, et al. No increased risk of tuberculosis-related immune reconstitution inflammatory syndrome with integrase inhibitor-based antiretroviral therapy in people with HIV with profound immunosuppression. HIV Med [Internet]. 2024 Aug 12; Available from: http://dx.doi.org/10.1111/hiv.13695 Zhao Y, Hohlfeld A, Namale P, Meintjes G, Maartens G, Engel ME. Risk of immune reconstitution inflammatory syndrome with integrase inhibitors versus other classes of antiretrovirals: A systematic review and meta-analysis of randomized trials. J Acquir Immune Defic Syndr. 2022 Jun 1;90(2):232–9. Pérez-Valero I, Corona D, Martínez N, López-Cavanillas M, Lluis C, Luque I. Real-world discontinuations due to neuropsychiatric symptoms in people living with HIV treated with second-generation integrase inhibitors: a systematic review. Expert Rev Anti Infect Ther. 2023 Jun;21(6):655–65. Senneker T, Tseng A. An update on neuropsychiatric adverse effects with second-generation integrase inhibitors and nonnucleoside reverse transcriptase inhibitors. Curr Opin HIV AIDS. 2021 Nov 1;16(6):309–20. Cuzin L, Pugliese P, Katlama C. Dat’AIDS Study Group. Integrase strand transfer inhibitors and neuropsychiatric adverse events in a large prospective cohort. Additional Declarations Competing interest reported. CB: Research grants: CNPq, GSK, Pfizer, Janssen. All but CNPq grants were awarded to Fundação Bahiana de Infectologia; Speaker and Advisory board (Gilead, GSK, MSD); SCW: Advisory Boar (ViiV); VM: Speaker (GSK, Gilead, Janssen); ANB: Speaker (Abbvie, Amgen-Bergamo, Astrazeneca, Boehringer Ingelheim, Celltrion, Dr. Reedys, Eurofarma, Gilead, GSK-ViiV, Janssen, Knigth Therapeutics, Moderna, MSD, Pfizer, Procter Gamble, Roche, Sanofi Pasteur, S. C. Johnson Johnson, Takeda, e Wyeth); KP: Has received research grants from the U.S. National Institutes of Health, and U.S. Centers for Disease Control and Prevention. All grants were awarded to the University of New Mexico. RZ: GSK employee; BJ: ViiV Healthcare employee. Supplementary Files CODEProtocolSTROBEchecklistv4cohort.doc Strobe checklist Cite Share Download PDF Status: Published Journal Publication published 08 Oct, 2025 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 31 Mar, 2025 Reviews received at journal 29 Mar, 2025 Reviews received at journal 29 Mar, 2025 Reviewers agreed at journal 25 Mar, 2025 Reviewers agreed at journal 20 Mar, 2025 Reviewers agreed at journal 19 Mar, 2025 Reviewers invited by journal 05 Feb, 2025 Editor assigned by journal 29 Jan, 2025 Submission checks completed at journal 29 Jan, 2025 First submitted to journal 28 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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DST/AIDS","correspondingAuthor":false,"prefix":"","firstName":"Valdez","middleName":"","lastName":"Madruga","suffix":""},{"id":408644295,"identity":"81d91721-82cb-4c42-8f71-bad6a63597d4","order_by":8,"name":"Tânia Reuter","email":"","orcid":"","institution":"Hospital Universitário Cassiano Antônio de Moraes","correspondingAuthor":false,"prefix":"","firstName":"Tânia","middleName":"","lastName":"Reuter","suffix":""},{"id":408644296,"identity":"bee0f7c7-6416-494c-b292-18c799ac0a6a","order_by":9,"name":"Alexandre Naime Barbosa","email":"","orcid":"","institution":"Universidade Estadual Paulista","correspondingAuthor":false,"prefix":"","firstName":"Alexandre","middleName":"Naime","lastName":"Barbosa","suffix":""},{"id":408644297,"identity":"00a55ff3-8d7d-4a7e-a93c-09938ca7d040","order_by":10,"name":"Rosa Dea Speahack","email":"","orcid":"","institution":"Fundação Universidade de Caxias do Sul","correspondingAuthor":false,"prefix":"","firstName":"Rosa","middleName":"Dea","lastName":"Speahack","suffix":""},{"id":408644298,"identity":"9b936396-c62c-42d8-bcb7-d95ca1167d84","order_by":11,"name":"Monica Baumgardt Bay","email":"","orcid":"","institution":"Universidade Federal do Rio Grande do Norte","correspondingAuthor":false,"prefix":"","firstName":"Monica","middleName":"Baumgardt","lastName":"Bay","suffix":""},{"id":408644299,"identity":"03906165-ebd3-4b51-ab2f-ba5caed33db9","order_by":12,"name":"Tâmara Newman","email":"","orcid":"","institution":"Instituto de Infectologia Emílio Ribas","correspondingAuthor":false,"prefix":"","firstName":"Tâmara","middleName":"","lastName":"Newman","suffix":""},{"id":408644300,"identity":"da7aae75-083f-462b-a58c-267d74fd5677","order_by":13,"name":"Karen Morejon","email":"","orcid":"","institution":"Hospital das Clínicas da Faculdade de Medicina de Ribeirao Preto, Universidade São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Karen","middleName":"","lastName":"Morejon","suffix":""},{"id":408644301,"identity":"fae8143a-0615-4067-91c4-ef686c630548","order_by":14,"name":"Maria Patelli","email":"","orcid":"","institution":"Sociedade Campineira de Educação e Instrução","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Patelli","suffix":""},{"id":408644302,"identity":"7ed93e4e-c556-4d63-b42f-34bfcce9b938","order_by":15,"name":"Fábio Leal","email":"","orcid":"","institution":"Universidade Municipal de São Caetano do Sul","correspondingAuthor":false,"prefix":"","firstName":"Fábio","middleName":"","lastName":"Leal","suffix":""},{"id":408644303,"identity":"46aff0de-2ba8-410c-9991-58dd0b980fbd","order_by":16,"name":"Eduardo Sprinz","email":"","orcid":"","institution":"Hospital de Clínicas de Porto 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Scenter","correspondingAuthor":false,"prefix":"","firstName":"Jess","middleName":"","lastName":"Anderson","suffix":""},{"id":408644307,"identity":"72937f94-b9ba-4788-958c-821e0bfd2e00","order_by":20,"name":"Alejandro Aragon","email":"","orcid":"","institution":"University of New Mexico Health Sciences Scenter","correspondingAuthor":false,"prefix":"","firstName":"Alejandro","middleName":"","lastName":"Aragon","suffix":""},{"id":408644308,"identity":"cd9f5c97-e4e1-46d1-a719-7abbe69c3921","order_by":21,"name":"Benjamin Chase","email":"","orcid":"","institution":"University of New Mexico Health Sciences Scenter","correspondingAuthor":false,"prefix":"","firstName":"Benjamin","middleName":"","lastName":"Chase","suffix":""},{"id":408644309,"identity":"0d6922f0-8b3d-4b17-8ac8-d562e1279883","order_by":22,"name":"Roberto Zajdenverg","email":"","orcid":"","institution":"Glaxo Smith-Kleine","correspondingAuthor":false,"prefix":"","firstName":"Roberto","middleName":"","lastName":"Zajdenverg","suffix":""},{"id":408644310,"identity":"35fdee48-eb0c-4634-965a-e785b73c4e10","order_by":23,"name":"Bryn Jones","email":"","orcid":"","institution":"ViiV Healthcare","correspondingAuthor":false,"prefix":"","firstName":"Bryn","middleName":"","lastName":"Jones","suffix":""},{"id":408644311,"identity":"17cfff36-4e8c-4afe-b1ca-6c4a01003061","order_by":24,"name":"Fatima Dutra","email":"","orcid":"","institution":"University of New Mexico Health Sciences Scenter","correspondingAuthor":false,"prefix":"","firstName":"Fatima","middleName":"","lastName":"Dutra","suffix":""},{"id":408644312,"identity":"35837d8f-08ab-45cc-b429-eb526b986dcd","order_by":25,"name":"Kimberly Page","email":"","orcid":"","institution":"University of New Mexico Health Sciences Scenter","correspondingAuthor":false,"prefix":"","firstName":"Kimberly","middleName":"","lastName":"Page","suffix":""}],"badges":[],"createdAt":"2025-01-28 13:23:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5918947/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5918947/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-025-11700-0","type":"published","date":"2025-10-08T15:57:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":75189442,"identity":"69d3af1e-5038-4c27-b213-bd919eec1af2","added_by":"auto","created_at":"2025-01-31 18:03:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":152133,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClinical sites for the CODE Study.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5918947/v1/6ad875780f9c62a38b0b6d7c.png"},{"id":75189444,"identity":"bcf1573a-caa2-4d50-9275-c1e3d935f266","added_by":"auto","created_at":"2025-01-31 18:03:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":63091,"visible":true,"origin":"","legend":"\u003cp\u003eCode Consort Diagram (as of 01 September 2024)\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5918947/v1/825b7582c74b48c6bf97d96a.png"},{"id":93419708,"identity":"33953797-96d0-42e1-b96c-693cd375e0ea","added_by":"auto","created_at":"2025-10-13 16:06:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1140915,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5918947/v1/c0e56310-f644-4e6a-866e-5723dcce9a1b.pdf"},{"id":75189443,"identity":"f3a11e4e-0a5e-4a8e-ac1a-1d5c3a7ef2b3","added_by":"auto","created_at":"2025-01-31 18:03:43","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":88064,"visible":true,"origin":"","legend":"\u003cp\u003eStrobe checklist\u003c/p\u003e","description":"","filename":"CODEProtocolSTROBEchecklistv4cohort.doc","url":"https://assets-eu.researchsquare.com/files/rs-5918947/v1/2bcd4f6b756b516445dec388.doc"}],"financialInterests":"Competing interest reported. CB: Research grants: CNPq, GSK, Pfizer, Janssen. All but CNPq grants were awarded to Fundação Bahiana de Infectologia; Speaker and Advisory board (Gilead, GSK, MSD); SCW: Advisory Boar (ViiV); VM: Speaker (GSK, Gilead, Janssen); ANB: Speaker (Abbvie, Amgen-Bergamo, Astrazeneca, Boehringer Ingelheim, Celltrion, Dr. Reedys, Eurofarma, Gilead, GSK-ViiV, Janssen, Knigth Therapeutics, Moderna, MSD, Pfizer, Procter Gamble, Roche, Sanofi Pasteur, S. C. Johnson Johnson, Takeda, e Wyeth); KP: Has received research grants from the U.S. National Institutes of Health, and U.S. Centers for Disease Control and Prevention. All grants were awarded to the University of New Mexico. RZ: GSK employee; BJ: ViiV Healthcare employee.","formattedTitle":"Clinical outcomes of Dolutegravir treatment in people living with HIV in Brazil: Protocol for the CODE Cohort","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe rapid expansion of access to antiretroviral therapy (ART) in low- and middle-income countries has been a significant milestone in the global fight against HIV. In Brazil, where ART has been universally available since 1996, the recent introduction of Dolutegravir (DTG)-based regimens as first-line therapy represents a critical advancement. The World Health Organization (WHO) guidelines now recommend DTG, combined with two nucleoside reverse transcriptase inhibitors (NRTIs) such as tenofovir and lamivudine, as the preferred regimen for initiating ART. (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) However, despite the advantages of DTG, including its virologic potency, high barrier to resistance, and favorable tolerability profile, there remain critical gaps in understanding its long-term outcomes, particularly in real-world settings.\u003c/p\u003e \u003cp\u003eThe CODE cohort study is designed to address these gaps by providing robust data on the clinical outcomes of DTG-based ART in a large cohort of people living with HIV in Brazil. This multicenter, prospective observational study will follow ART-na\u0026iuml;ve patients starting DTG-based regimens, those switching to DTG due to virological failure, and a comparator group of patients who initiated non-DTG-based ART before DTG was introduced in Brazil.\u003c/p\u003e \u003cp\u003eSeveral specific concerns have emerged from recent studies that highlight the need for further investigation. For example, the rapid virologic suppression associated with integrase inhibitors (INIs) like DTG has been linked to an increased risk of immune reconstitution inflammatory syndrome (IRIS), particularly among patients with low CD4 cell counts at ART initiation, although other reports showed no difference in comparison with regimens based in other antiretroviral drugs. In European cohorts, INI-based regimens have been associated with a 2\u0026ndash;3 fold increase in IRIS risk among patients with CD4 counts below 200 cells/mm\u0026sup3;. Moreover, observational studies have pointed to variable rates of DTG discontinuation due to central nervous system (CNS) and metabolic toxicities.(\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) Given these potential risks, there is an urgent need to understand the broader implications of DTG use, especially as it becomes more widely available in settings with a high burden of late-stage HIV and co-infections like tuberculosis.\u003c/p\u003e \u003cp\u003eThe Brazilian context offers a unique opportunity to study these issues. With a large and diverse population of people living with HIV, Brazil's healthcare system provides a natural laboratory for evaluating the real-life effectiveness and safety of DTG-based regimens. The CODE study aims to quantify the frequency of DTG discontinuation due to adverse events, evaluate virological suppression rates, assess clinical outcomes such as IRIS, weight gain, and CNS effects, and identify the development of drug resistance in patients on DTG-based therapy.\u003c/p\u003e \u003cp\u003eThis study will follow a cohort of 5000 participants over 36 months, including 2500 ART-na\u0026iuml;ve individuals, 1000 ART patients switching to DTG for various reasons, and a retrospective cohort of 1500 individuals never took DTG. The broad inclusion criteria and diverse participant population will allow for a comprehensive assessment of DTG's impact across various stages of HIV infection and treatment histories.\u003c/p\u003e \u003cp\u003eIn summary, the CODE cohort study is poised to provide critical insights into the real-world outcomes of DTG-based ART in Brazil. By addressing the knowledge gaps related to DTG's safety and effectiveness, this study will contribute valuable evidence to guide treatment strategies in similar low- and middle-income country settings worldwide.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAim, Design, and Setting\u003c/h2\u003e \u003cp\u003eThe CODE cohort study is a multicenter, prospective observational study designed to assess the clinical outcomes of people living with HIV who are initiating or switching to Dolutegravir (DTG)-based antiretroviral therapy (ART) in Brazil. The study is conducted across multiple clinical sites, including major HIV treatment centers in the cities of Rio de Janeiro, Salvador, S\u0026atilde;o Paulo, and Porto Alegre. Additional sites include clinics and hospitals in Caxias do Sul, Ribeir\u0026atilde;o Preto, Vitoria, Nova Igua\u0026ccedil;u, Campinas, S\u0026atilde;o Caetano do Sul, Natal and Botucatu (See Fig.\u0026nbsp;1)\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Population and Sample Size\u003c/h3\u003e\n\u003cp\u003eThe study aims to enroll a total of 5000 participants, distributed across four groups: Group 1 includes 2500 ART-na\u0026iuml;ve individuals starting a DTG-based regimen; Group 2 includes 500 patients on stable ART who switch to DTG-based regimens for any reason, and Group 3 includes 500 ART-experienced patients switching to DTG due to virological failure on their current regimen. The fourth Group (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) is a comparator group that includes data from 1500 patients who initiated non-DTG-based ART between 2013 and 2016 and have not switched to a DTG regimen. Participants will be followed for up to 36 months, with data collection points at baseline, 6, 12, 24, and 36 months. This large and diverse sample size is designed to ensure sufficient power to detect differences in clinical outcomes between the groups, particularly in terms of treatment discontinuation, virological suppression, and the incidence of adverse events.\u003c/p\u003e\n\u003ch3\u003eInclusion and Exclusion Criteria\u003c/h3\u003e\n\u003cp\u003eInclusion Criteria include: 1) documented HIV infection by plasma HIV RNA viral load, rapid HIV test, or any licensed ELISA test. If diagnosis was made by rapid or serological test a confirmation by an alternative method such as Western Blot, HIV culture, or HIV pro-viral DNA is required; 2) age\u0026thinsp;\u0026ge;\u0026thinsp;15 years; and 3) initiation of a DTG-based regimen or for the comparator Group 4, a non-DTG-based ART regimen between 2013 and 2016. In the three prospective groups, women of child-bearing potential must be willing to use effective contraceptive methods. Patients are excluded from the drug-naive Group 1 if they have previously used ART. Persons incarcerated or on compulsory detention for psychiatric or physical illness are excluded.\u003c/p\u003e\n\u003ch3\u003eParticipant Selection and Recruitment\u003c/h3\u003e\n\u003cp\u003eParticipants are being recruited from the clinical sites based on their eligibility and willingness to participate in the study. The selection process will ensure a heterogeneous population reflective of the broader HIV-positive population in Brazil. The broad inclusion criteria are designed to capture a wide range of patient characteristics, allowing for subgroup analyses and the identification of factors associated with specific outcomes.\u003c/p\u003e\n\u003ch3\u003eStudy Procedures\u003c/h3\u003e\n\u003cp\u003eAt baseline, all prospective participants will undergo comprehensive assessments, including: collection of demographic data (e.g., age, gender, education level); documentation of HIV infection status, including CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;cell counts, and HIV RNA levels. A detailed medical history, including prior ART use, co-infections, and other relevant health conditions and a physical examination that includes weight, height, abdominal circumference, and blood pressure is taken. Laboratory evaluations include complete blood count (CBC), liver and renal function tests, fasting glucose and lipid profile, and urinalysis for proteinuria and blood samples are collected for plasma storage to facilitate future resistance testing. Finally, a Quality-of-Life assessment using the WHO QoL BREF is conducted for those switching to DTG-based regimens. Participants will be followed at 6, 12, 24, and 36 months (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). During these visits, the following will be monitored: continued documentation of ART regimen and any changes, including reasons for switching or discontinuation; clinical evaluations, including measurement of vital signs, weight, and assessment of any new symptoms or adverse events; repeat laboratory tests to monitor HIV RNA levels, CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;counts, markers of liver and renal function, and assessments of adherence to ART, and any concomitant medications. For those switching to DTG-based regimens, quality of life assessments are conducted at 6 and 12 months.\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\u003eSchedule of assessments for prospective Groups 1, 2, and 3.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRequirement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e*Baseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e \u003cp\u003eFollow-up visits\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36 months\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInformed consent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographics, including education\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDocumentation of HIV infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD4\u0026thinsp;+\u0026thinsp;cell count and CD4% / CD8\u0026thinsp;+\u0026thinsp;cell count and CD8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTargeted health history and clinical evaluation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecord of the highest CD4\u0026thinsp;+\u0026thinsp;cell count (absolute and %) and HIV RNA documented in the medical record at any time in the past.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFindings from genotyping or other form of acceptable ART resistance testing, if available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecording of selected concomitant medications (see item 3.5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePregnancy status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQuality of life assessment (switch group)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of alcohol and recreational drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnthropometric measures**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlasma Sample Storage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHIV RNA level\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCBC: hemoglobin, hematocrit, white blood cell count (WBC) with differential and platelets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal function measurement: serum creatinine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver function measurements: ALT, AST, alkaline phosphatase, total bilirubin and albumin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cholesterol, LDL, HDL, triglycerides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDipstick urinalysis for protein\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDEXA and / or the assessment of body fat impedance (whenever possible)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e*(\u0026lt;\u0026thinsp;60 days before participant\u0026acute;s study)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e** Anthropometric measurements (weight, abdominal waist, hips and height (height only on visit 1).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e*** If possible.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e# 60 days before or after the scheduled date.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eParticipants in Group 4 are identified from existing clinical databases and patient records across the participating sites. Eligible participants must have initiated non-DTG-based ART within the specified timeframe (2013\u0026ndash;2016) and must have adequate medical records that allow for the extraction of relevant clinical data. Inclusion criteria focus on ensuring that participants have consistent follow-up data available over the study period, with particular attention to ART regimen details, clinical outcomes, and laboratory results. Baseline data is extracted for each participant from the time of ART initiation, and includes: demographic information, baseline CD4 count, HIV RNA levels, and any comorbid conditions present at the time of ART initiation (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Baseline data also include details of the initial ART regimen, reasons for selecting the non-DTG-based regimen, and any contraindications to DTG that may have influenced treatment decisions. Follow-up data collection for this group corresponds to the same intervals used for the prospective groups: at 6, 12, 24, and 36 months after ART initiation, and includes: virological, immunological, clinical outcomes, adverse events and treatment modifications (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\u003eSchedule of assessments for Restropective Arm (Group 4)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRequirement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e*Baseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e \u003cp\u003eFollow-up visits\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36 months\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInformed consent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDocumentation of HIV infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD4\u0026thinsp;+\u0026thinsp;cell count and CD4% / CD8\u0026thinsp;+\u0026thinsp;cell count and CD8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTargeted health history and clinical evaluation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecord of the highest CD4\u0026thinsp;+\u0026thinsp;cell count (absolute and %) and HIV RNA documented in the medical record at any time in the past.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFindings from genotyping or other form of acceptable ART resistance testing, if available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecording of selected concomitant medications (see item 3.5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePregnancy status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of alcohol and recreational drugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnthropometric measures**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHIV RNA level\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCBC: hemoglobin, hematocrit, white blood cell count (WBC) with differential and platelets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal function measurement: serum creatinine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver function measurements: ALT, AST, alkaline phosphatase, total bilirubin and albumin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cholesterol, LDL, HDL, triglycerides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDipstick urinalysis for protein\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e*(\u0026lt;\u0026thinsp;60 days before participant\u0026acute;s study)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e** Anthropometric measurements (weight, abdominal waist, hips and height (height only on visit 1).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e*** If possible.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e# 60 days before or after the scheduled date.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAdverse events (AEs) and serious adverse events (SAEs) are recorded and reported according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (Version 2.1). All SAEs will be reported to the study sponsor (ViiV Healthcare) and Institutional Review Boards (IRBs) within 24 hours of awareness.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData Management\u003c/h2\u003e \u003cp\u003eData will be collected and managed using the Research Electronic Data Capture (REDCap) system hosted at the University of New Mexico (UNM). REDCap is a secure, web-based application designed to support data capture for research studies, providing an interface for validated data entry, audit trails, and automated export procedures. The system includes encryption, password protection, and internal quality controls to ensure the accuracy and completeness of data. Each clinical site will be responsible for entering data into REDCap, with regular monitoring and quality checks conducted by the study\u0026rsquo;s Statistics and Data Coordinating Center (SDCC) at UNM.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003ePrimary Analysis: The primary outcome is the proportion of treatment-na\u0026iuml;ve participants (Group 1) who discontinue DTG-based ART due to any event within 12 months, compared to those who initiated non-DTG-based ART (Group 4). This will be analyzed using a modified multivariable Poisson model, adjusting for potential confounders such as age, gender, race, and baseline CD4 count.\u003c/p\u003e \u003cp\u003eSecondary Analysis: Secondary outcomes include virological suppression rates, changes in body mass index (BMI), incidence of IRIS, and the development of drug resistance. These will be assessed using similar multivariable model, as well as linear mixed models for continuous outcomes such as BMI changes.\u003c/p\u003e \u003cp\u003eExploratory Analysis: Exploratory outcomes, such as the frequency of cardiovascular events, new-onset diabetes, and quality of life changes, will be analyzed descriptively and use appropriate statistical tests for between-group comparisons.\u003c/p\u003e \u003cp\u003eHandling of Missing Data: Given the observational nature of the study, missing data is expected. The analysis will include strategies such as multiple imputation for missing data assumed to be missing at random (MAR) or completely at random (MCAR). Sensitivity analyses will be conducted to assess the impact of missing data on the study\u0026rsquo;s findings.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthical Considerations\u003c/h3\u003e\n\u003cp\u003e The study is being conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines, and local regulatory requirements. Ethical approval has been obtained from the IRBs at each participating site, and all participants will provide written informed consent prior to enrollment. Confidentiality will be maintained using coded identifiers, and data will be stored in secure, access-controlled databases. The study also includes provisions for the protection of vulnerable populations, such as adolescents and women of child-bearing potential.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatus And Timeline Of The Study\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents a Consort Diagram of enrolled and followed patients, missed and pending visits, and number of withdrawals. As of September 1st, 2024, the CODE study has a total of 4,288 patients enrolled. Baseline data has been collected for 2,077 patients in Group 1, 508 in Group 2, 188 in Group 3, and 1,515 in Group 4. Six month visits have been completed for 67.3% (1398/2077), 91.5% (465/508), and 63.3% (119/188) patients in Groups 1, 2, and 3 respectively. Group 4 has completed 6 month data for 85.3% of 1515 patients enrolled. Data is also shown for the 12, 24, and 36 month visits.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe CODE cohort study provides a unique opportunity to investigate the real-world outcomes of DTG-based ART among people living with HIV in Brazil. As a large, multicenter prospective observational study, CODE is poised to generate valuable data on the efficacy and safety of DTG-based regimens, particularly in diverse populations that may be underrepresented in randomized controlled trials. We expect this study will yield critical insights into the long-term outcomes of DTG-based ART, including the rates of treatment discontinuation due to adverse events, virological suppression, and the development of drug resistance. The primary finding of interest\u0026mdash;the proportion of ART-na\u0026iuml;ve patients who discontinue DTG-based regimens\u0026mdash;will provide essential information on the tolerability of DTG in real-world settings. Secondary outcomes, such as the frequency of metabolic and psychiatric events, will help elucidate the broader safety profile of DTG. The inclusion of ART-experienced patients and a retrospective comparator cohort of individuals on non-DTG regimens enhances the study's relevance by enabling a comparison across different treatment histories and clinical contexts. This will allow us to identify specific subgroups who may be at higher risk for adverse outcomes or who might benefit the most from DTG-based therapy.\u003c/p\u003e \u003cp\u003eWhile the study's observational design offers the advantage of capturing real-world data, it also presents certain limitations that must be acknowledged. First, the non-randomized nature of the study may introduce selection bias, as patients initiating DTG-based therapy may differ systematically from those on other regimens. We have attempted to mitigate this by using broad inclusion criteria and adjusting for potential confounders in our statistical analyses. However, residual confounding cannot be entirely ruled out. Another potential limitation is the reliance on clinical sites across different regions of Brazil, which may lead to variability in data collection practices and clinical management. To address this, we have implemented standardized protocols for data collection and adverse event monitoring, along with regular quality assurance checks conducted by the UNM SDCC. Missing data is an inherent challenge in any longitudinal study, particularly in a cohort as large and diverse as CODE. We have taken steps to minimize missing data through rigorous follow-up procedures and will use appropriate statistical techniques, such as multiple imputation, to handle any missing data that does occur. The historical control group, which is the study\u0026rsquo;s comparator group may introduce bias, due to potential differences in patient populations and data quality. However, Brazilian guidelines for HIV treatment limit creation of a different control group using a different contemporary regimen. Finally, the observational nature of the study limits our ability to establish causal relationships between DTG use and the outcomes of interest. While we can identify associations, further studies, including randomized controlled trials, may be needed to confirm these findings and explore underlying mechanisms.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eFuture Research Directions\u003c/h2\u003e \u003cp\u003eThe findings from the CODE cohort study are expected to inform future research and clinical practice in several important ways. First, they will provide much-needed data on the safety and effectiveness of DTG in diverse populations, including those with late-stage HIV or co-infections such as tuberculosis and viral hepatitis. This is particularly relevant for low- and middle-income countries, where such data are often lacking.\u003c/p\u003e \u003cp\u003eSecond, the study's focus on real-world outcomes, such as treatment discontinuation and the development of drug resistance, will contribute to a better understanding of the long-term implications of DTG use in routine clinical practice. This could lead to the refinement of treatment guidelines and the development of strategies to optimize the use of DTG in different patient populations.\u003c/p\u003e \u003cp\u003eIn addition to the immediate findings, the CODE study will create a valuable biorepository of plasma samples that can be used for future research on HIV drug resistance and other virological and immunological outcomes. This resource will facilitate ongoing investigations into the mechanisms of DTG resistance and the identification of biomarkers for adverse outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eDissemination and Impact\u003c/h2\u003e \u003cp\u003eThe results of the CODE cohort study will be disseminated through peer-reviewed publications, conference presentations, and reports to national and international health agencies. We aim to share our findings with a wide audience, including clinicians, researchers, policymakers, and community stakeholders, to maximize the study's impact on HIV treatment and care.\u003c/p\u003e \u003cp\u003eGiven the global shift towards DTG-based regimens, particularly in resource-limited settings, the findings from CODE are expected to have significant implications for the management of HIV worldwide. By providing robust, real-world data on the safety and effectiveness of DTG, the study will contribute to the evidence base needed to guide treatment decisions and improve patient outcomes.\u003c/p\u003e \u003cp\u003eIn conclusion, the CODE cohort study represents a critical step forward in our understanding of DTG-based ART in diverse and often underrepresented populations. While the study has certain limitations, its strengths lie in its large, multicenter design, comprehensive data collection, and focus on real-world outcomes. The knowledge gained from this study will be invaluable in shaping the future of HIV treatment in Brazil and beyond.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003eEthics approval and consent to participate\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eEthical approval has been obtained from the IRBs at each participating site, and all participants will provide written informed consent prior to enrollment.\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eConsent for publication\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eNot aplicable\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eAvailability of data and materials\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eCompeting interests\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eCB:\u0026nbsp;Research grants: CNPq, GSK, Pfizer, Janssen. All but CNPq grants were awarded to Funda\u0026ccedil;\u0026atilde;o Bahiana de Infectologia; Speaker and Advisory board (Gilead, GSK, MSD); SCW: Advisory Boar (ViiV); VM: Speaker (GSK, Gilead, Janssen); ANB: Speaker (Abbvie, Amgen-Bergamo, Astrazeneca, Boehringer Ingelheim, Celltrion, Dr. Reedys, Eurofarma, Gilead, GSK-ViiV, Janssen, Knigth Therapeutics, Moderna, MSD, Pfizer, Procter Gamble, Roche, Sanofi Pasteur, S. C. Johnson Johnson, Takeda, e Wyeth); KP: Has received research grants from the U.S. National Institutes of Health, and U.S. Centers for Disease Control and Prevention. All grants were awarded to the University of New Mexico. RZ: GSK employee; BJ: ViiV Healthcare employee.\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eFunding\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe study was funded by a grant from ViiV Healthcare/GSK Brazil (GSK-212964) received by Funda\u0026ccedil;\u0026atilde;o Bahiana de Infectologia\u003c/p\u003e\n\u003cp\u003eAuthor contributions: CB and KP conceptualized the study and study design. \u0026nbsp;CB, KP, CM-K, JE, MC, AA, and BC developed the data collection methods, and analytic approach. All Brazilian authors (CB, EL, CS, FB, MVGL, AR,SW, VM, TR, AN, RDS, MBB, TN, KM, MP, FL, ES) are involved in data collection. The manuscript was written by KP, CB and CM-K, and all other authors reviewed and provided input and editing to the writing. \u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eAcknowledgements\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;Acknowledgements: \u0026nbsp;We acknowledge the following individuals who contributed expertise and assistance for the study: Benjamin Chase for early data management assistance, and Mariana Herring for expert translation and communication services.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSupporting information: Strobe checklist\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMinisterio de Saude B. Protocolo Cl\u0026iacute;nico e Diretrizes Terap\u0026ecirc;uticas para Manejo da Infec\u0026ccedil;\u0026atilde;o pelo HIV em Adultos, 2024 [Internet]. 2024. Available from: https://bvsms.saude.gov.br/bvs/publicacoes/ pcdt_manejo_hiv_adultos_modulo1.pdf. Accessed in September, 06, 2024\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. WHO recommends dolutegravir as preferred HIV treatment option in all populations [Internet]. 2023. Available from: https://www.who.int/news/item/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-option-in-all-populations.Accessed. Accessed September 06, 2024.\u003c/li\u003e\n\u003cli\u003eAprilianti S, Utami AM, Suwantika AA, Zakiyah N, Azis VI. The cost-effectiveness of dolutegravir in combination with tenofovir and lamivudine for HIV therapy: A systematic review. Clinicoecon Outcomes Res. 2024 Jan 26;16:25\u0026ndash;34.\u003c/li\u003e\n\u003cli\u003eWijting I, Wit F, Rokx C. ATHENA national observational HIV cohort. ATHENA national observational HIV cohort.\u003c/li\u003e\n\u003cli\u003eGaillet A, Calin R, Flandre P, Tubiana R, Valantin M-A, Caumes E, et al. Increased risk of IRIS-associated tuberculosis in HIV-infected patients receiving Integrase Inhibitors. Infect Dis Now. 2021 Feb;51(1):90\u0026ndash;3.\u003c/li\u003e\n\u003cli\u003eChan CK, Huang SS, Wong KH, Leung CC, Lee MP, Tsang TY, et al. No increased risk of tuberculosis-related immune reconstitution inflammatory syndrome with integrase inhibitor-based antiretroviral therapy in people with HIV with profound immunosuppression. HIV Med [Internet]. 2024 Aug 12; Available from: http://dx.doi.org/10.1111/hiv.13695\u003c/li\u003e\n\u003cli\u003eZhao Y, Hohlfeld A, Namale P, Meintjes G, Maartens G, Engel ME. Risk of immune reconstitution inflammatory syndrome with integrase inhibitors versus other classes of antiretrovirals: A systematic review and meta-analysis of randomized trials. J Acquir Immune Defic Syndr. 2022 Jun 1;90(2):232\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eP\u0026eacute;rez-Valero I, Corona D, Mart\u0026iacute;nez N, L\u0026oacute;pez-Cavanillas M, Lluis C, Luque I. Real-world discontinuations due to neuropsychiatric symptoms in people living with HIV treated with second-generation integrase inhibitors: a systematic review. Expert Rev Anti Infect Ther. 2023 Jun;21(6):655\u0026ndash;65.\u003c/li\u003e\n\u003cli\u003eSenneker T, Tseng A. An update on neuropsychiatric adverse effects with second-generation integrase inhibitors and nonnucleoside reverse transcriptase inhibitors. Curr Opin HIV AIDS. 2021 Nov 1;16(6):309\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eCuzin L, Pugliese P, Katlama C. Dat\u0026rsquo;AIDS Study Group. Integrase strand transfer inhibitors and neuropsychiatric adverse events in a large prospective cohort.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5918947/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5918947/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe Clinical Outcomes of Dolutegravir Treatment in People Living with HIV in Brazil (CODE) cohort study is a multicenter, prospective, observational study designed to evaluate the safety and efficacy of Dolutegravir (DTG)-based antiretroviral therapy (ART) among people living with HIV across diverse settings in Brazil. With the recent global shift towards DTG as a preferred option for first-line ART, particularly in low- and middle-income countries, there is vital need for comprehensive real-world data to inform its widespread use. CODE aims to fill this knowledge gap by assessing the clinical outcomes of both ART-na\u0026iuml;ve and ART-experienced patients initiating DTG-based regimens, as well as those who have switched from non-DTG-based ART. The primary objective of this study is to determine the proportion of patients who discontinue DTG due to any adverse events, specifically focusing on metabolic and psychiatric outcomes. Secondary objectives include evaluating the rates of virological suppression, the occurrence of immune reconstitution inflammatory syndrome (IRIS), changes in body mass index (BMI), and the development of HIV drug resistance. The CODE cohort will enroll approximately 5000 participants from multiple clinical sites across Brazil, including 2500 ART-na\u0026iuml;ve individuals, 1000 patients switching to DTG-based regimens for various reasons, and a comparator group of 1500 individuals who initiated non-DTG-based ART between 2013 and 2016, before DTG was available in the country. Participants will be followed for up to 36 months, with data collection points at baseline, 6, 12, 24, and 36 months. This study is expected to generate critical insights into the long-term outcomes associated with DTG-based ART, particularly in real-world settings that reflect the complexities of routine clinical care. By providing robust data on the effectiveness and safety of DTG in a diverse patient population, the CODE study aims to contribute to the optimization of HIV treatment strategies both in Brazil and globally.\u003c/p\u003e","manuscriptTitle":"Clinical outcomes of Dolutegravir treatment in people living with HIV in Brazil: Protocol for the CODE Cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-31 18:03:39","doi":"10.21203/rs.3.rs-5918947/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-31T13:31:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-29T23:29:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-29T20:26:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"181811999574121252326161023888783915674","date":"2025-03-25T13:50:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"111558248485144091641184075511138880246","date":"2025-03-20T12:09:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"154916094744977599696164861948876320676","date":"2025-03-19T15:57:47+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-02-05T16:32:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-29T12:57:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-29T12:55:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-01-28T13:12:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3138fa28-a2b3-46f1-8589-f0a52c939fca","owner":[],"postedDate":"January 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-13T16:00:43+00:00","versionOfRecord":{"articleIdentity":"rs-5918947","link":"https://doi.org/10.1186/s12879-025-11700-0","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2025-10-08 15:57:29","publishedOnDateReadable":"October 8th, 2025"},"versionCreatedAt":"2025-01-31 18:03:39","video":"","vorDoi":"10.1186/s12879-025-11700-0","vorDoiUrl":"https://doi.org/10.1186/s12879-025-11700-0","workflowStages":[]},"version":"v1","identity":"rs-5918947","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5918947","identity":"rs-5918947","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}