Changes in Weight, Body Composition and Cardiac Risk After Discontinuing Abacavir Treatment in HIV-infected Individuals (AVERTAS-1)

Changes in Weight and Body Composition After Switch to Dolutegravir/Lamivudine Compared to Continued Dolutegravir/Abacavir/Lamivudine for Virologically Suppressed HIV Infection: A Randomized Open-label Superiority Trial: AVERTAS-1

Randomized controlled parallel open-label study in people living with HIV and at least 6 month of treatment with dolutegravir/abacavir/lamivudine prior to inclusion.

Participants (n=95) are randomized to continue 3 drug-regimen dolutegravir/abacavir/lamivudine (control) or switch to two-drug regimen with dolutegravir/lamivudine (intervention). Follow-up is 48 weeks. Data is collected at baseline and week 48. Primary outcome is changes in weight from baseline of more than 2 kg. Secondary outcomes are changes in cardiac risk, composition and calcification of the heart tissue, and changes in body composition and metabolism, inflammation and coagulation. A MRI substudy is applied to focus on the cardiac adverse effects of abacavir.

Study Overview

• Status: Recruiting
• Conditions: Cardiovascular Diseases; HIV Infections; Hiv; Weight Change, Body; HIV Lipodystrophy; HIV Cardiomyopathy
• Intervention / Treatment: Drug: Dolutegravir / Lamivudine Oral Tablet

Detailed Description

In the MRI sub study 40 patients from the main study (20 from each group) are included. A cardiac MRI are performed at baseline and week 48 to evaluate cardiac effects of abacavir.

• Study Type: Interventional
• Enrollment (Anticipated): 95
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Karen BH Pedersen, MD; Phone Number: +4521623027; Email: karen.brorup.heje.pedersen@regionh.dk
• Study Contact Backup: Name: Thomas L Benfield, MD, DMSc; Email: thomas.lars.benfield@regionh.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Not yet recruiting
    • Aalborg University Hospital
    • Contact: Henrik Nielsen, MD, DMSc
  • Aarhus, Denmark, 8200
    • Not yet recruiting
    • Aarhus University Hospital
    • Contact: Alex L Laursen, MD, DMSc
  • Copenhagen, Denmark, 2100
    • Not yet recruiting
    • Rigshospitalet
    • Contact: Jan Gerstoft, MD, DMSc
  • Hvidovre, Denmark, 2650
    • Recruiting
    • Copenhagen University Hospital, Amager Hvidovre
    • Contact: Thomas Benfield, MD; Phone Number: 38622302; Email: thomas.lars.benfield@regionh.dk
    • Contact: Karen Brorup Pedersen, MD; Email: karen.brorup.heje.pedersen@regionh.dk
  • Odense, Denmark, 5000
    • Not yet recruiting
    • Odense University Hospital
    • Contact: Isik S Johansen, MD, DMSc

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• ≥ 18 years old
• Diagnosed HIV
• At least 6 months of ongoing treatment with dolutegravir/ abacavir/lamivudine
• Plasma viral load (HIV-RNA) < 50 copies/ml at inclusion

For women of childbearing potential:

• Negative pregnancy test
• Willingness to use contraceptive (consistent with local regulations) during study period

Exclusion Criteria:

• Pre-existing viral resistance mutations to lamivudine or to dolutegravir
• Presence of hepatitis B antigen (HBsAg) or Hepatitis B virus DNA (HBV DNA)
• Cancer within past 5 years
• Diabetes, cardiovascular disease or other chronic illness considered stable as assessed by the treating physician

For women of childbearing potential:

• Pregnancy
• Breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: dolutegravir/lamivudine; 50 mg dolutegravir and 300 mg lamivudine (co-formulated) once daily for 48 weeks	Drug: Dolutegravir / Lamivudine Oral Tablet; Discontinuing abacavir by switching from three-drug regimen with dolutegravir/abacavir/lamivudine to two-drug regimen with dolutegravir/lamivudine; Other Names: Dolutegravir/abacavir/lamivudine
No Intervention: dolutegravir/abacavir/lamivudine; 50 mg dolutegravir, 600 mg abacavir and 300 mg lamivudine (co-formulated) once daily for 48 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in body weight of ≥2 kg	Fasting body weight	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virological control	HIV-RNA <50 copies/ml	48 weeks
Changes in self-rated health	12-item Short Form Health Survey (SF-12). Scores from 0 (worse) to 100 (best).	48 weeks
Change in metabolism	Impaired insulin resistance and/or β-cell function determined by changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)	48 weeks
Changes in cardiac risk	D:A:D CVD risk score: Five and ten years predicted cardio vascular disease risk (percent)	48 weeks
Changes in carotid artery intima-media thickness (cIMT)	Measured by ultrasound.	48 weeks
Changes in Coronary artery calcium score (CACS)	Measures by CT-scan. Scores from 0 and with no upper limit. The higher score, the worse calcification/plaque level and higher CVD risk.	48 weeks
Changes in cardiac blood markers	Changes in N-terminal pro-B-type natriuretic peptide (Pro-BNP)	48 weeks
Changes in bloodpressure	Systolic and diastolic blood pressure (mmHg)	48 weeks
Changes in fat distribution VAT/SAT	Measured by CT-scan • Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) determined by abdominal CT.	48 weeks
Changes in liver stiffness	Measured by CT-scan and liver elastography	48 weeks
Changes in liver fat infiltration	Measured by CT-scan and liver elastography	48 weeks
Changes in fat distribution in trunk, limb and extremities	Measured by dual energy xray absorptiometry (DEXA)	48 weeks
Changes in inflammation	High-sensitive C-reactive protein	48 weeks
Changes in interleukins	Interleukin 1- and interleukin 6	48 weeks
Changes in endothelial function	Vascular cell adhesion molecule 1 and intercellular adhesion molecule 1	48 weeks
Changes in soluble P-selectin	soluble P-selectin	48 weeks
Changes in soluble glycoprotein VI	soluble glycoprotein VI	48 weeks
Changes in d-dimer	D-dimer	48 weeks
Changes in coagulation	Factor 2, 7 and 10 (extrinsic pathway)	48 weeks
Changes in fibrinogen	Fibrinogen	48 weeks
Changes in blood Hemoglobin	Hemoglobin	48 weeks
Changes in blood platelets	Platelets	48 weeks
Changes in plasma creatinine	Creatinine	48 weeks
Changes in plasma urea	Urea	48 weeks
Changes in plasma sodium	Sodium	48 weeks
Changes in plasma potassium	Potassium	48 weeks
Changes in plasma bilirubin	Bilirubin	48 weeks
Changes in plasma alanine	Alanine	48 weeks
Changes in plasma aminotransferase	Aminotransferase	48 weeks
Cardiovascular risk	Framingham risk score: Estimated 10 years risk of cardiovascular disease (percent)	48 weeks
Cardiac biomarkers	Changes in Troponin T (TnT)	48 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac MRI substudy primary outcome (composite) ECV	Cardiac MRI applied on 40 patients to evaluate: Decrease in extracellular myocardial volume (ECV) from baseline to week 48	48 weeks
Cardiac MRI substudy primary outcome (composite) atrial volume	Cardiac MRI applied on 40 patients to evaluate: Decrease in left atrial volume from baseline to week 48	48 weeks
Cardiac MRI substudy primary outcome (composite) diastolic function	Cardiac MRI applied on 40 patients to evaluate: Improvement in diastolic function from baseline to week 48	48 weeks
Cardiac MRI substudy primary outcome (composite) myocardial mass	Cardiac MRI applied on 40 patients to evaluate: Reduction in myocardial mass from baseline to week 48	48 weeks
Cardiac MRI substudy secondary outcome ejection fraction (EF)	Cardiac MRI applied on 40 patients to evaluate: Secondary outcomes Changes in: • Ejection fraction (EF)	48 weeks
Cardiac MRI substudy secondary outcome perfusion	Cardiac MRI applied on 40 patients to evaluate: Secondary outcomes Changes in: • Perfusion	48 weeks
Cardiac MRI substudy secondary outcome edema/inflammation	Cardiac MRI applied on 40 patients to evaluate: Secondary outcomes Changes in: • Edema/inflammation	48 weeks
Cardiac MRI substudy secondary outcome fibrosis	Cardiac MRI applied on 40 patients to evaluate: Secondary outcomes Changes in: • Fibrosis	48 weeks
Cardiac MRI substudy secondary outcome lipid	Cardiac MRI applied on 40 patients to evaluate: Secondary outcomes Changes in: • Lipid-water profile Measured by MR spectroscopy	48 weeks

Collaborators and Investigators

• Sponsor: Thomas Benfield
• Investigators: Principal Investigator: Thomas Benfield, MD, DMSc, Department of Infectious diseases, Hvidovre Hospital, Denmark

Publications and helpful links

General Publications

• Belloso WH, Orellana LC, Grinsztejn B, Madero JS, La Rosa A, Veloso VG, Sanchez J, Ismerio Moreira R, Crabtree-Ramirez B, Garcia Messina O, Lasala MB, Peinado J, Losso MH. Analysis of serious non-AIDS events among HIV-infected adults at Latin American sites. HIV Med. 2010 Oct 1;11(9):554-64. doi: 10.1111/j.1468-1293.2010.00824.x. Epub 2010 Mar 21.
• Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P, Kowalska JD, de Wit S, Law M, el Sadr W, Kirk O, Friis-Moller N, Monforte Ad, Phillips AN, Sabin CA, Lundgren JD; D:A:D Study Group. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet. 2014 Jul 19;384(9939):241-8. doi: 10.1016/S0140-6736(14)60604-8.
• Freiberg MS, Chang CC, Kuller LH, Skanderson M, Lowy E, Kraemer KL, Butt AA, Bidwell Goetz M, Leaf D, Oursler KA, Rimland D, Rodriguez Barradas M, Brown S, Gibert C, McGinnis K, Crothers K, Sico J, Crane H, Warner A, Gottlieb S, Gottdiener J, Tracy RP, Budoff M, Watson C, Armah KA, Doebler D, Bryant K, Justice AC. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013 Apr 22;173(8):614-22. doi: 10.1001/jamainternmed.2013.3728.
• Sabin CA, Reiss P, Ryom L, Phillips AN, Weber R, Law M, Fontas E, Mocroft A, de Wit S, Smith C, Dabis F, d'Arminio Monforte A, El-Sadr W, Lundgren JD; D:A:D Study Group. Is there continued evidence for an association between abacavir usage and myocardial infarction risk in individuals with HIV? A cohort collaboration. BMC Med. 2016 Mar 31;14:61. doi: 10.1186/s12916-016-0588-4.
• Worm SW, Sabin C, Weber R, Reiss P, El-Sadr W, Dabis F, De Wit S, Law M, Monforte AD, Friis-Moller N, Kirk O, Fontas E, Weller I, Phillips A, Lundgren J. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis. 2010 Feb 1;201(3):318-30. doi: 10.1086/649897.
• D:A:D Study Group, Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, De Wit S, Law M, D'Arminio Monforte A, Friis-Moller N, Kirk O, Pradier C, Weller I, Phillips AN, Lundgren JD. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008 Apr 26;371(9622):1417-26. doi: 10.1016/S0140-6736(08)60423-7. Epub 2008 Apr 2. Erratum In: Lancet. 2008 Jul 26;372(9635):292.
• Venter WDF, Moorhouse M, Sokhela S, Fairlie L, Mashabane N, Masenya M, Serenata C, Akpomiemie G, Qavi A, Chandiwana N, Norris S, Chersich M, Clayden P, Abrams E, Arulappan N, Vos A, McCann K, Simmons B, Hill A. Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV. N Engl J Med. 2019 Aug 29;381(9):803-815. doi: 10.1056/NEJMoa1902824. Epub 2019 Jul 24.
• Lake JE, Wu K, Bares SH, Debroy P, Godfrey C, Koethe JR, McComsey GA, Palella FJ, Tassiopoulos K, Erlandson KM. Risk Factors for Weight Gain Following Switch to Integrase Inhibitor-Based Antiretroviral Therapy. Clin Infect Dis. 2020 Dec 3;71(9):e471-e477. doi: 10.1093/cid/ciaa177.
• Hill A, Waters L, Pozniak A. Are new antiretroviral treatments increasing the risks of clinical obesity? J Virus Erad. 2019 Jan 1;5(1):41-43.
• Sax PE, Erlandson KM, Lake JE, Mccomsey GA, Orkin C, Esser S, Brown TT, Rockstroh JK, Wei X, Carter CC, Zhong L, Brainard DM, Melbourne K, Das M, Stellbrink HJ, Post FA, Waters L, Koethe JR. Weight Gain Following Initiation of Antiretroviral Therapy: Risk Factors in Randomized Comparative Clinical Trials. Clin Infect Dis. 2020 Sep 12;71(6):1379-1389. doi: 10.1093/cid/ciz999.
• Choi AI, Vittinghoff E, Deeks SG, Weekley CC, Li Y, Shlipak MG. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS. 2011 Jun 19;25(10):1289-98. doi: 10.1097/QAD.0b013e328347fa16.
• Desai M, Joyce V, Bendavid E, Olshen RA, Hlatky M, Chow A, Holodniy M, Barnett P, Owens DK. Risk of cardiovascular events associated with current exposure to HIV antiretroviral therapies in a US veteran population. Clin Infect Dis. 2015 Aug 1;61(3):445-52. doi: 10.1093/cid/civ316. Epub 2015 Apr 22.
• O'Halloran JA, Dunne E, Tinago W, Denieffe S, Kenny D, Mallon PWG. Switching from abacavir to tenofovir disoproxil fumarate is associated with rises in soluble glycoprotein VI, suggesting changes in platelet-collagen interactions. AIDS. 2018 Apr 24;32(7):861-866. doi: 10.1097/QAD.0000000000001783.
• Freiberg MS, Chang CH, Skanderson M, Patterson OV, DuVall SL, Brandt CA, So-Armah KA, Vasan RS, Oursler KA, Gottdiener J, Gottlieb S, Leaf D, Rodriguez-Barradas M, Tracy RP, Gibert CL, Rimland D, Bedimo RJ, Brown ST, Goetz MB, Warner A, Crothers K, Tindle HA, Alcorn C, Bachmann JM, Justice AC, Butt AA. Association Between HIV Infection and the Risk of Heart Failure With Reduced Ejection Fraction and Preserved Ejection Fraction in the Antiretroviral Therapy Era: Results From the Veterans Aging Cohort Study. JAMA Cardiol. 2017 May 1;2(5):536-546. doi: 10.1001/jamacardio.2017.0264.
• Thiara DK, Liu CY, Raman F, Mangat S, Purdy JB, Duarte HA, Schmidt N, Hur J, Sibley CT, Bluemke DA, Hadigan C. Abnormal Myocardial Function Is Related to Myocardial Steatosis and Diffuse Myocardial Fibrosis in HIV-Infected Adults. J Infect Dis. 2015 Nov 15;212(10):1544-51. doi: 10.1093/infdis/jiv274. Epub 2015 May 11.
• Luetkens JA, Doerner J, Schwarze-Zander C, Wasmuth JC, Boesecke C, Sprinkart AM, Schmeel FC, Homsi R, Gieseke J, Schild HH, Rockstroh JK, Naehle CP. Cardiac Magnetic Resonance Reveals Signs of Subclinical Myocardial Inflammation in Asymptomatic HIV-Infected Patients. Circ Cardiovasc Imaging. 2016 Mar;9(3):e004091. doi: 10.1161/CIRCIMAGING.115.004091.
• Ntusi N, O'Dwyer E, Dorrell L, Wainwright E, Piechnik S, Clutton G, Hancock G, Ferreira V, Cox P, Badri M, Karamitsos T, Emmanuel S, Clarke K, Neubauer S, Holloway C. HIV-1-Related Cardiovascular Disease Is Associated With Chronic Inflammation, Frequent Pericardial Effusions, and Probable Myocardial Edema. Circ Cardiovasc Imaging. 2016 Mar;9(3):e004430. doi: 10.1161/CIRCIMAGING.115.004430.
• Friis-Moller N, Thiebaut R, Reiss P, Weber R, Monforte AD, De Wit S, El-Sadr W, Fontas E, Worm S, Kirk O, Phillips A, Sabin CA, Lundgren JD, Law MG; DAD study group. Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study. Eur J Cardiovasc Prev Rehabil. 2010 Oct;17(5):491-501. doi: 10.1097/HJR.0b013e328336a150.
• Hsue PY, Hunt PW, Ho JE, Farah HH, Schnell A, Hoh R, Martin JN, Deeks SG, Bolger AF. Impact of HIV infection on diastolic function and left ventricular mass. Circ Heart Fail. 2010 Jan;3(1):132-9. doi: 10.1161/CIRCHEARTFAILURE.109.854943. Epub 2009 Nov 20.
• Hutchins E, Wang R, Rahmani S, Nakanishi R, Haberlen S, Kingsley L, Witt MD, Palella FJ Jr, Jacobson L, Budoff MJ, Post WS. HIV Infection Is Associated with Greater Left Ventricular Mass in the Multicenter AIDS Cohort Study. AIDS Res Hum Retroviruses. 2019 Aug;35(8):755-761. doi: 10.1089/AID.2019.0014. Epub 2019 Jun 3.
• Erqou S, Lodebo BT, Masri A, Altibi AM, Echouffo-Tcheugui JB, Dzudie A, Ataklte F, Choudhary G, Bloomfield GS, Wu WC, Kengne AP. Cardiac Dysfunction Among People Living With HIV: A Systematic Review and Meta-Analysis. JACC Heart Fail. 2019 Feb;7(2):98-108. doi: 10.1016/j.jchf.2018.10.006.

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2020
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: October 9, 2020
• First Submitted That Met QC Criteria: May 26, 2021
• First Posted (Actual): May 27, 2021

Study Record Updates

• Last Update Posted (Actual): May 27, 2021
• Last Update Submitted That Met QC Criteria: May 26, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Cardiovascular disease; HIV; Antiretroviral Therapy; Weight changes; Antiretroviral therapy side effects; Antiretroviral two-drug regimen; HIV metabolism; HIV diabetes
• Additional Relevant MeSH Terms: Heart Diseases; Metabolic Diseases; Skin Diseases; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Lipid Metabolism Disorders; Slow Virus Diseases; Skin Diseases, Metabolic; HIV Infections; Cardiovascular Diseases; Infections; Body Weight; Acquired Immunodeficiency Syndrome; Cardiomyopathies; Body Weight Changes; Lipodystrophy; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Lamivudine; Dolutegravir; Abacavir
• Other Study ID Numbers: H-20011433

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