Changes in Weight, Body Composition and Metabolic Parameters After Discontinuing Dolutegravir or Tenofovir Disproxil (AVERTAS-2)

Changes in Weight After Switch to Dolutegravir/Lamivudine or Doravirine/Tenofovir/Lamivudine Compared to Continued Treatment With Dolutegravir/Tenofovir/Lamivudine for Virologically Suppressed HIV Infection. AVERTAS-2

Randomized controlled parallel open-label study in persons living with HIV. The aim is to study weight changes in patients switching from a dolutegravir and tenofovir disoproxil containing regimen to either a dolutegravir or tenofovir disoproxil free regimen.

Study Overview

• Status: Recruiting
• Conditions: HIV Infections; Obesity; Renal Insufficiency; Osteoporosis; Hiv; Weight Gain; HIV Lipodystrophy
• Intervention / Treatment: Drug: Dolutegravir/Lamivudine 50 MG-300 MG Oral Tablet [DOVATO]; Drug: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 100 MG-300 MG-300 MG Oral Tablet [DELSTRIGO]

Detailed Description

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

Participants (n=126) are randomized to continue 3 drug-regimen dolutegravir/tenofovir disoproxil/lamivudine (control) or switch to two-drug regimen with dolutegravir/lamivudine (intervention 1) or to three-drug regimen with doravirine/tenofovir disoproxil/lamivudine. 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 virus persistent viral suppression, changes in body composition and metabolism, changes in bone metabolisme and renal function, changes in liver elasticity and fat infiltration.

• Study Type: Interventional
• Enrollment (Anticipated): 126
• 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 Benfield, MD; Email: thomas.lars.benfield@regionh.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Not yet recruiting
    • Department of Infectious Diseases, Aalborg University Hospital
    • Contact: Henrik Nielsen, MD, DMSc
  • Aarhus, Denmark, 8200
    • Not yet recruiting
    • Department of Infectious Diseases, Aarhus University Hospital
    • Contact: Alex L Laursen, MD, PhD
  • Copenhagen, Denmark, 2100
    • Not yet recruiting
    • Department of Infectious Diseases, Rigshospitalet
    • Contact: Jan Gerstoft, MD, DMSc
  • Hvidovre, Denmark, 2650
    • Recruiting
    • Department of Infectious Diseases, Hvidovre University Hospital
    • Contact: Karen BH Pedersen, MD; Phone Number: +4521623027; Email: karen.brorup.heje.pedersen@regionh.dk
  • Odense, Denmark, 5000
    • Not yet recruiting
    • Department of Infectious Diseases, 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:

• Individuals ≥ 18 years old with diagnosed HIV and at least 6 months of ongoing treatment with dolutegravir/ doravirin/lamivudine will be included. Patients must have a plasma viral load (HIV-RNA) < 50 copies/ml at inclusion. For women of childbearing potential: Negative pregnancy test and willingness to use contraceptive (consistent with local regulations) during study period

Exclusion Criteria:

• Patients will be excluded in case of pre-existing viral resistance mutations to lamivudine, dolutegravir, tenofovir or doravirine the presence of hepatitis B antigen (HBsAg) or HBV DNA, cancer within past 5 years, pregnancy or breastfeeding. Any case of diabetes, cardiovascular disease or other chronic illness must be considered stable as assessed by the treating physician.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Dolutegravir/tenofovir disproxil/lamivudine; Continue dolutegravir 50 mg, tenofovir disproxil 245 mg, ,and lamivudine 300 mg once daily for 48 weeks.
Experimental: dolutegravir/lamivudine; dolutegravir 50 mg/lamivudine 300 mg once daily for 48 weeks	Drug: Dolutegravir/Lamivudine 50 MG-300 MG Oral Tablet [DOVATO]; Two-drug therapy; Other Names: Dovato
Experimental: doravirine/tenofovir disproxil/lamivudine; 100 mg doravirin, 245 mg tenofovirdisoproxil and 300 mg lamivudine once daily for 48 weeks.	Drug: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 100 MG-300 MG-300 MG Oral Tablet [DELSTRIGO]; Three-drug therapy; Other Names: Delstrigo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body weight	Primary outcome is a change in body weight of more than 2 kg from	48 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virological control	Plasma HIV-RNA <50 copies/ml	48 weeks
Self-rated health	Changes in 12-item Short Form Health Survey (SF-12). Scores from 0 (worse) to 100 (best).	48 weeks
Insulin resistance	Impaired insulin resistance and/or β-cell function determined by changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)	48 weeks
Diabetic profile	Changes in HbA1c	48 weeks
Cholesterol profile	Changes in cholesterol total, HDL, LDL, VLDL	48 weeks
Fat distribution	Changes in Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) determined by thoracic and upper abdominal CT-scan.	48 weeks
Hepatic elasticity	Changes in hepativ elasticity determined by liver elastography (Fibro-scan)	48 weeks
Hepatic fat infiltration	Changes in hepatic fat infiltration determined by liver elastography (Fibro-scan) and upper abdominal CT-scan	48 weeks
Body composition/perfiferal and central fat distribution	Changes in body fat distribtuion determined bu Dual Energy X-ray Absorbtiometry (DEXA)	48 weeks
Estimated Glomerular Filtration Rate (eGFR) (creatinine)	Changes in eGFR estimated by plasma creatinine	48 weeks
eGFR (cystatin)	Changes in estimated by plasma cystatin	48 weeks
Urea	Changes in plasma urea	48 weeks
Urine RBP/creatinine ratio	Changes in Urine RBP/creatinine ratio determined by spot urine Retinol Binding Protein (RBP) and creatinine analysis	48 weeks
Urine Beta-2-Microglobulin(B2M)/creatinine ratio	Changes in B2M/creatinine ratio determined by spot urine B2M and creatinine	48 weeks
Urine albumin/creatinine ratio	Changes in Urine albumin/creatinine ratio determined by spot urine albumine and creatinine analysis	48 weeks
Urine protein/creatinine ratio	Changes in urine protein/creatinine ratio determined by spot urine protein and creatinine analysis	48 weeks
Urine phosphate	Changes in spot urine phosphate	48 weeks
Bone mass density (BMD)	Changes in BMD assessed by DEXA	48 weeks
Bone-specific alkaline phosphate	Changes in plasma Bone-specific alkaline phosphate	48 weeks
Procollagen type 1 N-pro-peptide	Changes in procollagen type 1 N-pro-peptide	48 weeks
Type 1 collagen cross-linked C-telopeptide	Changes in plasma Type 1 collagen cross-linked C-telopeptide	48 weeks
Osteocalcin	Changes in plasma osteocalcin	48 weeks
Fasting ionized calcium	Changes in plasma fasting ionized calcium	48 weeks
25(OH)vitamin D vitamin D 25(OH)vitamin D	Changes in plasma 25(OH)vitamin D	48 weeks
Parathyroid hormone (PTH) vitamin D 25(OH)vitamin D	Changes in plasma parathyroid hormone (PTH)	48 weeks
Inflammation	High-sensitive C-reactive protein	48 weeks

Collaborators and Investigators

• Sponsor: Thomas Benfield
• Investigators: Study Director: Thomas Benfield, MD, Center of Research and Disruption of Infectious Diseases

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.
• 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.
• Brown TT, Cole SR, Li X, Kingsley LA, Palella FJ, Riddler SA, Visscher BR, Margolick JB, Dobs AS. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med. 2005 May 23;165(10):1179-84. doi: 10.1001/archinte.165.10.1179. Erratum In: Arch Intern Med. 2005 Nov 28;165(21):2541.
• Koethe JR, Jenkins CA, Lau B, Shepherd BE, Justice AC, Tate JP, Buchacz K, Napravnik S, Mayor AM, Horberg MA, Blashill AJ, Willig A, Wester CW, Silverberg MJ, Gill J, Thorne JE, Klein M, Eron JJ, Kitahata MM, Sterling TR, Moore RD; North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Rising Obesity Prevalence and Weight Gain Among Adults Starting Antiretroviral Therapy in the United States and Canada. AIDS Res Hum Retroviruses. 2016 Jan;32(1):50-8. doi: 10.1089/aid.2015.0147. Epub 2015 Sep 9.
• Bakal DR, Coelho LE, Luz PM, Clark JL, De Boni RB, Cardoso SW, Veloso VG, Lake JE, Grinsztejn B. Obesity following ART initiation is common and influenced by both traditional and HIV-/ART-specific risk factors. J Antimicrob Chemother. 2018 Aug 1;73(8):2177-2185. doi: 10.1093/jac/dky145.
• Burns JE, Stirrup OT, Dunn D, Runcie-Unger I, Milinkovic A, Candfield S, Lukha H, Severn A, Waters L, Edwards S, Gilson R, Pett SL. No overall change in the rate of weight gain after switching to an integrase-inhibitor in virologically suppressed adults with HIV. AIDS. 2020 Jan 1;34(1):109-114. doi: 10.1097/QAD.0000000000002379.
• Vizcarra P, Vivancos MJ, Perez-Elias MJ, Moreno A, Casado JL. Weight gain in people living with HIV switched to dual therapy: changes in body fat mass. AIDS. 2020 Jan 1;34(1):155-157. doi: 10.1097/QAD.0000000000002421.
• Nartey ET, Tetteh RA, Yankey BA, Mantel-Teeuwisse AK, Leufkens HGM, Dodoo ANO, Lartey M. Tenofovir-associated renal toxicity in a cohort of HIV infected patients in Ghana. BMC Res Notes. 2019 Jul 22;12(1):445. doi: 10.1186/s13104-019-4454-2.
• Nishijima T, Kawasaki Y, Tanaka N, Mizushima D, Aoki T, Watanabe K, Kinai E, Honda H, Yazaki H, Tanuma J, Tsukada K, Teruya K, Kikuchi Y, Gatanaga H, Oka S. Long-term exposure to tenofovir continuously decrease renal function in HIV-1-infected patients with low body weight: results from 10 years of follow-up. AIDS. 2014 Aug 24;28(13):1903-10. doi: 10.1097/QAD.0000000000000347.
• Casado JL, Santiuste C, Vazquez M, Banon S, Rosillo M, Gomez A, Perez-Elias MJ, Caballero C, Rey JM, Moreno S. Bone mineral density decline according to renal tubular dysfunction and phosphaturia in tenofovir-exposed HIV-infected patients. AIDS. 2016 Jun 1;30(9):1423-31. doi: 10.1097/QAD.0000000000001067.
• Gupta SK, Yeh E, Kitch DW, Brown TT, Venuto CS, Morse GD, Ha B, Melbourne K, McComsey GA. Bone mineral density reductions after tenofovir disoproxil fumarate initiation and changes in phosphaturia: a secondary analysis of ACTG A5224s. J Antimicrob Chemother. 2017 Jul 1;72(7):2042-2048. doi: 10.1093/jac/dkx076.
• Jacobson DL, Spiegelman D, Knox TK, Wilson IB. Evolution and predictors of change in total bone mineral density over time in HIV-infected men and women in the nutrition for healthy living study. J Acquir Immune Defic Syndr. 2008 Nov 1;49(3):298-308. doi: 10.1097/QAI.0b013e3181893e8e.

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2021
• Primary Completion (Anticipated): February 2, 2023
• Study Completion (Anticipated): February 2, 2023

Study Registration Dates

• First Submitted: October 9, 2020
• First Submitted That Met QC Criteria: May 21, 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 21, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: HIV; body composition; weight gain; antiretroviral therapy; fat distribution; antiretroviral therapy adverse events
• Additional Relevant MeSH Terms: 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; Kidney Diseases; Urologic Diseases; Musculoskeletal Diseases; Bone Diseases; Body Weight Changes; Lipid Metabolism Disorders; Slow Virus Diseases; Bone Diseases, Metabolic; Skin Diseases, Metabolic; HIV Infections; Infections; Renal Insufficiency; Body Weight; Acquired Immunodeficiency Syndrome; Osteoporosis; Weight Gain; 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; Tenofovir; Lamivudine; Dolutegravir
• Other Study ID Numbers: H-20012194

Drug and device information, study documents

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