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

• ClinicalTrials.gov Identifier: NCT04903847
• Recruitment Status: Recruiting
• First Posted: May 27, 2021
• Last Update Posted: May 27, 2021
• Sponsor: Thomas Benfield
• Information provided by (Responsible Party): Thomas Benfield, Hvidovre University Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hiv; HIV Infections; HIV Lipodystrophy; Osteoporosis; Renal Insufficiency; Weight Gain; Obesity	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]	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 126 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized controlled open-label superiority trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: February 2, 2021
• Estimated Primary Completion Date: February 2, 2023
• Estimated Study Completion Date: February 2, 2023

Arms and Interventions

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 Name: 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 Name: Delstrigo

Outcome Measures

Primary Outcome Measures :

1. Body weight [ Time Frame: 48 Weeks ]
   Primary outcome is a change in body weight of more than 2 kg from

Secondary Outcome Measures :

1. Virological control [ Time Frame: 48 weeks ]
   Plasma HIV-RNA <50 copies/ml
2. Self-rated health [ Time Frame: 48 weeks ]
   Changes in 12-item Short Form Health Survey (SF-12). Scores from 0 (worse) to 100 (best).
3. Insulin resistance [ Time Frame: 48 weeks ]
   Impaired insulin resistance and/or β-cell function determined by changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)
4. Diabetic profile [ Time Frame: 48 weeks ]
   Changes in HbA1c
5. Cholesterol profile [ Time Frame: 48 weeks ]
   Changes in cholesterol total, HDL, LDL, VLDL
6. Fat distribution [ Time Frame: 48 weeks ]
   Changes in Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) determined by thoracic and upper abdominal CT-scan.
7. Hepatic elasticity [ Time Frame: 48 weeks ]
   Changes in hepativ elasticity determined by liver elastography (Fibro-scan)
8. Hepatic fat infiltration [ Time Frame: 48 weeks ]
   Changes in hepatic fat infiltration determined by liver elastography (Fibro-scan) and upper abdominal CT-scan
9. Body composition/perfiferal and central fat distribution [ Time Frame: 48 weeks ]
   Changes in body fat distribtuion determined bu Dual Energy X-ray Absorbtiometry (DEXA)
10. Estimated Glomerular Filtration Rate (eGFR) (creatinine) [ Time Frame: 48 weeks ]
    Changes in eGFR estimated by plasma creatinine
11. eGFR (cystatin) [ Time Frame: 48 weeks ]
    Changes in estimated by plasma cystatin
12. Urea [ Time Frame: 48 weeks ]
    Changes in plasma urea
13. Urine RBP/creatinine ratio [ Time Frame: 48 weeks ]
    Changes in Urine RBP/creatinine ratio determined by spot urine Retinol Binding Protein (RBP) and creatinine analysis
14. Urine Beta-2-Microglobulin(B2M)/creatinine ratio [ Time Frame: 48 weeks ]
    Changes in B2M/creatinine ratio determined by spot urine B2M and creatinine
15. Urine albumin/creatinine ratio [ Time Frame: 48 weeks ]
    Changes in Urine albumin/creatinine ratio determined by spot urine albumine and creatinine analysis
16. Urine protein/creatinine ratio [ Time Frame: 48 weeks ]
    Changes in urine protein/creatinine ratio determined by spot urine protein and creatinine analysis
17. Urine phosphate [ Time Frame: 48 weeks ]
    Changes in spot urine phosphate
18. Bone mass density (BMD) [ Time Frame: 48 weeks ]
    Changes in BMD assessed by DEXA
19. Bone-specific alkaline phosphate [ Time Frame: 48 weeks ]
    Changes in plasma Bone-specific alkaline phosphate
20. Procollagen type 1 N-pro-peptide [ Time Frame: 48 weeks ]
    Changes in procollagen type 1 N-pro-peptide
21. Type 1 collagen cross-linked C-telopeptide [ Time Frame: 48 weeks ]
    Changes in plasma Type 1 collagen cross-linked C-telopeptide
22. Osteocalcin [ Time Frame: 48 weeks ]
    Changes in plasma osteocalcin
23. Fasting ionized calcium [ Time Frame: 48 weeks ]
    Changes in plasma fasting ionized calcium
24. 25(OH)vitamin D vitamin D 25(OH)vitamin D [ Time Frame: 48 weeks ]
    Changes in plasma 25(OH)vitamin D
25. Parathyroid hormone (PTH) vitamin D 25(OH)vitamin D [ Time Frame: 48 weeks ]
    Changes in plasma parathyroid hormone (PTH)
26. Inflammation [ Time Frame: 48 weeks ]
    High-sensitive C-reactive protein

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Karen BH Pedersen, MD; +4521623027; karen.brorup.heje.pedersen@regionh.dk

Contact: Thomas Benfield, MD; thomas.lars.benfield@regionh.dk

Locations

Denmark

Department of Infectious Diseases, Aalborg University Hospital; Not yet recruiting

Aalborg, Denmark, 9000

Contact: Henrik Nielsen, MD, DMSc

Department of Infectious Diseases, Aarhus University Hospital; Not yet recruiting

Aarhus, Denmark, 8200

Contact: Alex L Laursen, MD, PhD

Department of Infectious Diseases, Rigshospitalet; Not yet recruiting

Copenhagen, Denmark, 2100

Contact: Jan Gerstoft, MD, DMSc

Department of Infectious Diseases, Hvidovre University Hospital; Recruiting

Hvidovre, Denmark, 2650

Contact: Karen BH Pedersen, MD +4521623027 karen.brorup.heje.pedersen@regionh.dk

Department of Infectious Diseases, Odense University Hospital; Not yet recruiting

Odense, Denmark, 5000

Contact: Isik S Johansen, MD, DMSc

Sponsors and Collaborators

Thomas Benfield

Investigators

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

More Information

Publications:

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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.

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.

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.

• Responsible Party: Thomas Benfield, MD, professor, dr.med., Hvidovre University Hospital
• ClinicalTrials.gov Identifier: NCT04903847
• Other Study ID Numbers: H-20012194
• First Posted: May 27, 2021
• Last Update Posted: May 27, 2021
• Last Verified: May 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Thomas Benfield, Hvidovre University Hospital:

HIV; antiretroviral therapy; antiretroviral therapy adverse events; weight gain; body composition; fat distribution

Additional relevant MeSH terms:

Infections; HIV Infections; Acquired Immunodeficiency Syndrome; Osteoporosis; Renal Insufficiency; Lipodystrophy; Body Weight; Weight Gain; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Body Weight Changes; Kidney Diseases; Urologic Diseases; Skin Diseases, Metabolic; Skin Diseases; Lipid Metabolism Disorders; Tenofovir