Clinical trial NCT04904406: Changes in Weight, Body Composition and Cardiac Risk After Discontinuing Abacavir Treatment in HIV-infected Individuals
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hiv
HIV Infections
HIV Cardiomyopathy
Weight Change, Body
HIV Lipodystrophy
Cardiovascular Diseases
Keywords: HIV
Weight changes
Antiretroviral Therapy
Cardiovascular disease
Antiretroviral therapy side effects
Antiretroviral two-drug regimen
HIV metabolism
HIV diabetes
Lead sponsor: Hvidovre University Hospital
Sponsor class: OTHER
First posted: 2021-05-27
Enrollment: 81
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized controlled open-label superiority trial
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in body weight of ≥2 kg
timeFrame: 48 weeks
Secondary outcomes:
measure: Virological control
timeFrame: 48 weeks
measure: Changes in self-rated health
timeFrame: 48 weeks
measure: Change in metabolism
timeFrame: 48 weeks
measure: Changes in cardiac risk
timeFrame: 48 weeks
measure: Changes in carotid artery intima-media thickness (cIMT)
timeFrame: 48 weeks
measure: Changes in Coronary artery calcium score (CACS)
timeFrame: 48 weeks
measure: Changes in cardiac blood markers
timeFrame: 48 weeks
measure: Changes in bloodpressure
timeFrame: 48 weeks
measure: Changes in fat distribution VAT/SAT
timeFrame: 48 weeks
measure: Changes in liver stiffness
timeFrame: 48 weeks
measure: Changes in liver fat infiltration
timeFrame: 48 weeks
measure: Changes in fat distribution in trunk, limb and extremities
timeFrame: 48 weeks
measure: Changes in inflammation
timeFrame: 48 weeks
measure: Changes in interleukins
timeFrame: 48 weeks
measure: Changes in endothelial function
timeFrame: 48 weeks
measure: Changes in soluble P-selectin
timeFrame: 48 weeks
measure: Changes in soluble glycoprotein VI
timeFrame: 48 weeks
measure: Changes in d-dimer
timeFrame: 48 weeks
measure: Changes in coagulation
timeFrame: 48 weeks
measure: Changes in fibrinogen
timeFrame: 48 weeks
measure: Changes in blood Hemoglobin
timeFrame: 48 weeks
measure: Changes in blood platelets
timeFrame: 48 weeks
measure: Changes in plasma creatinine
timeFrame: 48 weeks
measure: Changes in plasma urea
timeFrame: 48 weeks
measure: Changes in plasma sodium
timeFrame: 48 weeks
measure: Changes in plasma potassium
timeFrame: 48 weeks
measure: Changes in plasma bilirubin
timeFrame: 48 weeks
measure: Changes in plasma alanine
timeFrame: 48 weeks
measure: Changes in plasma aminotransferase
timeFrame: 48 weeks
measure: Cardiovascular risk
timeFrame: 48 weeks
measure: Cardiac biomarkers
timeFrame: 48 weeks
Other outcomes:
measure: Cardiac MRI substudy primary outcome (composite) ECV
timeFrame: 48 weeks
measure: Cardiac MRI substudy primary outcome (composite) atrial volume
timeFrame: 48 weeks
measure: Cardiac MRI substudy primary outcome (composite) diastolic function
timeFrame: 48 weeks
measure: Cardiac MRI substudy primary outcome (composite) myocardial mass
timeFrame: 48 weeks
measure: Cardiac MRI substudy secondary outcome ejection fraction (EF)
timeFrame: 48 weeks
measure: Cardiac MRI substudy secondary outcome perfusion
timeFrame: 48 weeks
measure: Cardiac MRI substudy secondary outcome edema/inflammation
timeFrame: 48 weeks
measure: Cardiac MRI substudy secondary outcome fibrosis
timeFrame: 48 weeks
measure: Cardiac MRI substudy secondary outcome lipid
timeFrame: 48 weeks
Locations:
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital - Rigshospitalet
city: Hvidovre
country: Denmark
facility: Copenhagen University Hospital, Amager Hvidovre
Study officials:
affiliation: Department of Infectious diseases, Hvidovre Hospital, Denmark
name: Thomas Benfield, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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. doi: 10.1016/S2055-6640(20)30277-6.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.