Dolutegravir and Clinical Outcomes Among ART-recipients in Brazil (CODE)

Dolutegravir and Clinical Outcomes Among ART-recipients in Brazil: A Population-based Study

Access to antiretroviral therapy (ART) in low-income and middle-income countries has been scaled-up effectively over recent years. Recently, the World Health Organization (WHO) guidelines changed to recommend the use of Dolutegravir (DTG) combined with two nucleoside reverse transcriptase inhibitors (NRTIs), tenofovir and lamivudine, for first-line ART; however, there is still a need for further data on the outcomes of DTG-based regimens for people with HIV-1.

This study aims to describe the outcomes of drug-naïve and experienced patients starting a dolutegravir (DTG)-based regimen in a large cohort of HIV - infected patients in Brazil and compare to outcomes obtained from a retrospective control group of subjects who initiated non-DTG-based ART.

Study Overview

• Status: Recruiting
• Conditions: HIV Infections; Clinical Outcomes; Adverse Drug Event; Effect of Drugs
• Intervention / Treatment: Other: No intervention

Detailed Description

CODE is a multicenter prospective observational study to describe and quantify the outcomes of patients starting DTG-based regimens. The investigators will follow ART-naïve patients starting DTG-based regimens (Group 1), patients on stable ART regimens switching to DTG (any reason) (Group 2), and ART-experienced patients switching to DTG-containing regimens due to virological failure (Group 3). In addition, for comparison purposes, the investigators will collect data on patients who started a non-DTG containing regimen (Group 4) in the period for 2014-2016 and did not switch to DTG-based regimens (Figure 1). Enrolled patients will be followed for 36 months.

• Study Type: Observational
• Enrollment (Estimated): 5000

Contacts and Locations

• Study Contact: Name: Carlos Brites, MD, PhD; Phone Number: 557132838123; Email: crbrites@gmail.com
• Study Contact Backup: Name: Estela Luz, RN, MPH; Phone Number: 557132838123; Email: eluz5@yahoo.com.br

Study Locations

• Brazil
  • BA
    • Salvador, BA, Brazil, 40110160
      • Recruiting
      • Fundação Bahiana de Infectologia
      • Contact: Carlos Brites, MD, PhD; Email: crbrites@gmail.com
  • Bahia
    • Salvador, Bahia, Brazil, 40010-160
      • Recruiting
      • Fundação Bahiana de Infectologia/SEI
      • Contact: Estela Luz, RN, MSci; Phone Number: 32838123; Email: eluz5@yahoo.com.br
      • Principal Investigator: Carlos Brites, MD, PhD
      • Sub-Investigator: Polyanna Azevedo, MD
      • Sub-Investigator: Carolina Barbosa, MD
      • Sub-Investigator: Estela Luz, RN, MPH
  • SP
    • São Paulo, SP, Brazil, 04121-000
      • Recruiting
      • Centro de Referência e Treinamento
      • Contact: Valdez Madruga, MD; Email: valdezmr@uol.com.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

CODE is a multicenter prospective observational study to describe and quantify the outcomes of patients starting DTG-based regimens. The investigators will follow ART-naïve patients starting DTG-based regimens (Group 1), patients on stable ART regimens switching to DTG (any reason) (Group 2), and ART-experienced patients switching to DTG-containing regimens due to virological failure (Group 3). In addition, for comparison purposes, the investigators will collect data on patients who started a non-DTG containing regimen (Group 4) in the period for 2014-2016 and did not switch to DTG-based regimens (Figure 1).

Description

Inclusion Criteria:

• • Signed informed consent.

  • HIV infection documented by plasma HIV RNA viral load, a rapid HIV test or any licensed ELISA test; and confirmed by another test using a different method, including but not limited to a rapid HIV test, Western Blot, HIV culture, HIV antigen, or HIV pro-viral DNA at any time prior to study entry.
  • Age ≥ 15 years.
  • For women of child-bearing potential, willingness to use effective contraceptives.
  • Starting use of DTG-based regimen, or being initiated on a non-DTG based ART between 2014 - 2016.

Exclusion Criteria:

• • Any previous use of ART (drug-naïve group only).

  • Current imprisonment, or compulsory detention (involuntary incarceration). For treatment of a psychiatric or physical illness.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients starting DTG-based regimens; ART-naïve patients, starting cART regimens based on DTG	Other: No intervention; This will be an observational study, no intervention will be performed
Switch cohort; Patients on stable ART regimens switching to DTG (any reason)	Other: No intervention; This will be an observational study, no intervention will be performed
Therapy failure; ART-experienced patients switching to DTG-containing regimens due to virological failure	Other: No intervention; This will be an observational study, no intervention will be performed
Non-DTG group; Patients who started a non-DTG containing regimen	Other: No intervention; This will be an observational study, no intervention will be performed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
frequency of therapy discontinuation due to any event for patients starting ART	The key outcomes of interest include treatment discontinuation due to any event as well as specifically due to metabolic and psychiatric events, virologic outcomes (viral suppression at 12 months, failure to ART, and genotypic results of acquired resistance), clinical outcomes (including noted side effects, retention in care, death, weight changes, hyperglycemia, diabetes, lipid changes, AIDS-defining illnesses, and recorded psychiatric and CNS effects), and special outcomes / populations (pregnancy outcomes, IRIS events, changes in HRQoL, viral hepatitis flares, and tuberculosis outcomes)	36 months
therapy discontinuation due to any event for ART-eprerienced patients starting DTG-based regimens	therapy discontinuation due to any event for ART-experienced patients	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory outcomes	These clinical outcomes include: all-cause mortality; all AIDS-defining events; all types of cancer; bacterial pneumonia; pulmonary embolism; deep vein thrombosis; new-onset diabetes mellitus (as defined by the ADA criteria);10 coronary artery disease requiring drug treatment; congestive heart failure; peripheral vascular disease; fractures; and solicited adverse events.	36 months
Changes in quality of life for patients switching to DTG-based regimens	Physical and Mental Components Scores will be measured. HRQoL evaluation will be performed only for patients switching to DTG-based regimens, at the time switch occurs (baseline), and after 6 and 12 months of follow up.	6 and 12 months
HIV drug resistance	This outcome will be evaluated by collecting samples of blood prior to starting DTG-based ART. These tests will not be done in real time, and results will not be given to the investigator or participant. Once virological failure is identified, the baseline sample will be used to assess transmitted drug resistance through comparison with current resistance genotypic tests. Key mutations that are associated with viral resistance will be determined using information periodically updated by the International AIDS Society.	36 months
Markers of CVD risk	Assessments will be made of blood lipids, smoking, blood pressure, incidence of diabetes mellitus, use of medication to lower blood pressure and lipids, and the use of aspirin, to assist in the evaluation of cardiovascular risks and benefits of early treatment.	36 months

Collaborators and Investigators

• Sponsor: Fundação Bahiana de Infectologia
• Collaborators: Hospital de Clinicas de Porto Alegre; Universidade Federal do Rio Grande do Norte; University of New Mexico; Instituto Infectologia Evandro Chagas, Rio de Janeiro; Fundação de Medicina Tropical de Manaus; Centro de Referência e Tratamento, CRT, São Paulo, SP; Hospital Partenon, Porto Alegre; Universidade Municipal de São Caetano do Sul; Hospital Universitário Cassiano Antônio de Moraes/HUCAM; Hospital das Clínicas da Faculdade de Medicina de Ribeirao Preto/USP; Faculdade de Medicina de Botucatu, Unesp; Sociedade Campineira de Educação e Instrução - Campinas; Fundação Universidade de Caxias do Sul - FUCS/RS

Publications and helpful links

General Publications

• Dutertre M, Cuzin L, Demonchy E, Pugliese P, Joly V, Valantin MA, Cotte L, Huleux T, Delobel P, Martin-Blondel G; Dat'AIDS Study Group. Initiation of Antiretroviral Therapy Containing Integrase Inhibitors Increases the Risk of IRIS Requiring Hospitalization. J Acquir Immune Defic Syndr. 2017 Sep 1;76(1):e23-e26. doi: 10.1097/QAI.0000000000001397. No abstract available.
• de Boer MG, van den Berk GE, van Holten N, Oryszcyn JE, Dorama W, Moha DA, Brinkman K. Intolerance of dolutegravir-containing combination antiretroviral therapy regimens in real-life clinical practice. AIDS. 2016 Nov 28;30(18):2831-2834. doi: 10.1097/QAD.0000000000001279.
• Ciccullo A, Baldin G, Cossu MV, Passerini M, Borghetti A, Capetti A, Di Giambenedetto S. Dolutegravir Plus Lamivudine as First-Line Regimen in a Multicenter Cohort of HIV-1-Infected Patients: Preliminary Data from Clinical Practice. AIDS Res Hum Retroviruses. 2020 Jan;36(1):4-5. doi: 10.1089/AID.2019.0147. Epub 2019 Sep 30. No abstract available.
• Elzi L, Erb S, Furrer H, Cavassini M, Calmy A, Vernazza P, Gunthard H, Bernasconi E, Battegay M; Swiss HIV Cohort Study Group. Adverse events of raltegravir and dolutegravir. AIDS. 2017 Aug 24;31(13):1853-1858. doi: 10.1097/QAD.0000000000001590.
• Hoffmann C, Welz T, Sabranski M, Kolb M, Wolf E, Stellbrink HJ, Wyen C. Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. HIV Med. 2017 Jan;18(1):56-63. doi: 10.1111/hiv.12468. Epub 2016 Nov 10.
• Norwood J, Turner M, Bofill C, Rebeiro P, Shepherd B, Bebawy S, Hulgan T, Raffanti S, Haas DW, Sterling TR, Koethe JR. Brief Report: Weight Gain in Persons With HIV Switched From Efavirenz-Based to Integrase Strand Transfer Inhibitor-Based Regimens. J Acquir Immune Defic Syndr. 2017 Dec 15;76(5):527-531. doi: 10.1097/QAI.0000000000001525.
• Taramasso L, Ricci E, Menzaghi B, Orofino G, Passerini S, Madeddu G, Martinelli CV, De Socio GV, Squillace N, Rusconi S, Bonfanti P, Di Biagio A; CISAI Study Group. Weight Gain: A Possible Side Effect of All Antiretrovirals. Open Forum Infect Dis. 2017 Nov 3;4(4):ofx239. doi: 10.1093/ofid/ofx239. eCollection 2017 Fall.
• Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. N Engl J Med. 2018 Sep 6;379(10):979-981. doi: 10.1056/NEJMc1807653. Epub 2018 Jul 24. No abstract available.
• American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019 Jan;42(Suppl 1):S13-S28. doi: 10.2337/dc19-S002.
• Cruz LN, Fleck MP, Oliveira MR, Camey SA, Hoffmann JF, Bagattini AM, Polanczyk CA. Health-related quality of life in Brazil: normative data for the SF-36 in a general population sample in the south of the country. Cien Saude Colet. 2013 Jul;18(7):1911-21. doi: 10.1590/s1413-81232013000700006.
• Laguardia J, Campos MR, Travassos C, Najar AL, Anjos LA, Vasconcellos MM. Brazilian normative data for the Short Form 36 questionnaire, version 2. Rev Bras Epidemiol. 2013 Dec;16(4):889-97. doi: 10.1590/s1415-790x2013000400009. English, Portuguese.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): February 28, 2025

Study Registration Dates

• First Submitted: March 26, 2020
• First Submitted That Met QC Criteria: March 26, 2020
• First Posted (Actual): March 30, 2020

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Drug-Related Side Effects and Adverse Reactions
• Other Study ID Numbers: FBAI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No