Can INSTI-associated Weight Gain be Halted or Reversed With a Switch to Doravirine/Lamivudine/Tenofovir DF? (DeLiTE)

Can the Weight Gain Associated With Use of Integrase Strand Inhibitors be Halted or Reversed With a Switch to Doravirine/Lamivudine/Tenofovir DF in Patients Living With HIV? (DeLiTE)

Weight gain with the integrase inhibitors and tenofovir alafenamide has been observed in observational cohorts and randomized controlled clinical trials. Although some risk factors have been identified, the cause is unknown and it remains to be determined if the changes are reversible. The weight gain is of concern to persons living with HIV. This pilot intervention study is designed to provide preliminary data on whether switching patients with weight gain on an INSTI-based regimen to a combination of doravirine/tenofovir disoproxil fumarate/lamivudine (DOR/3TC/TDF, an NNRTI-based regimen) for one year can slow down or even reverse weight gain. These data will then be used to inform the design and sample size of a larger switch study.

Study Overview

• Status: Enrolling by invitation
• Conditions: Hiv; Weight Gain
• Intervention / Treatment: Drug: DOR/3TC/TDF

Detailed Description

Background and Importance: Lifelong antiretroviral treatment (ART) is recommended for all people living with HIV (PLWH) primarily with integrase strand inhibitor (INSTI)-based regimens. While weight gain following ART initiation was previously considered "return to health", recent studies have raised concerns of weight gain and increasing obesity in PLWH, most notably with INSTIs and possibly with tenofovir alafenamide (TAF), a preferred nucleoside backbone agent. The weight gain may be progressive and may increase cardiovascular risk. A critical unanswered question is whether weight gain and metabolic effects are permanent or reversible. This data is crucial to optimize ART therapy and health of PLWH.

Goal/Research Aims: No therapeutic alternatives are substantiated for ART-associated weight gain. Doravirine/lamivudine/tenofovir DF (DOR/3TC/TDF) is an attractive option to explore as it does not include an INSTI or TAF, is a well tolerated once daily single tablet, minimal drug interactions and has not been associated with significant weight gain to date. The investigators hypothesize that switching from an INSTI regimen to DOR/3TC/TDF will slow or reverse weight gain while maintaining viral suppression. Before embarking on a large randomized controlled study (RCT), the investigators propose this pilot study to determine the feasibility and acceptability and to obtain estimate measures of weight change to inform its design and sample size.

Methods: Open-label, exploratory pilot switch study. Patients who are virally suppressed on an INSTI regimen for >1 year, without ART resistance, and have experienced significant weight gain will be approached to switch to DOR/3TC/TDF for 48 weeks. Weight, adherence, viral load, CD4, and other relevant labs will be measured every 3 months. A DXA body scan and body image questionnaires will be completed at baseline and 12 months. The anticipated sample size is 25 with an aim to recruit 50% male, 50% female.

The primary objective is to determine what proportion of clinic patients meet eligibility criteria, agree to participate, and complete the study. The secondary objective is to estimate the distribution of various weight-related outcomes while on DOR/3TC/TDF compared to previous INSTI regimens. Exploratory outcomes will address metabolic changes and body image impact.

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G2C4
      • University Health Network

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:

• Documented HIV-1 infection by means of any one of the following:

Documentation of HIV diagnosis in the medical record by a licensed health care provider; OR HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating >1000 RNA copies/mL; OR any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 Western blot confirmation or HIV rapid Multispot antibody differentiation assay.

• On an Integrase Strand Transfer Inhibitor (INSTI) based regimen for at least 1 year and less than 5 years prior to screening
• Significant weight gain since initiation of the INSTI-based regimen (>10% of baseline body weight)
• Viral load of <200 copies/mL for > 6 consecutive months prior to screening (single viral blips <200 copies/mL accepted if re-suppressed)
• Documentation of weight, glycemia, cholesterol, and blood pressure (BP) history within the last year.
• Signed Informed Consent Form (Appendix B) and willing to comply with the protocol.
• Using proper contraception if of child bearing age and potential.

Exclusion Criteria:

• Pregnancy or desire to become pregnant within the next year
• Failure to use adequate contraception during the study if of child-bearing potential.
• Any underlying documented ART resistance to doravirine, tenofovir disoproxil fumarate, or lamivudine
• Prior virologic failure
• Concomitant drugs that interact with doravirine
• Initiated on concomitant drugs known to cause weight gain within the last 6 months (i.e. antidepressants and antipsychotics)
• Concomitant drugs known to cause nephrotoxicity
• History of renal toxicity or renal events while on TDF therapy.
• Creatinine clearance (CrCL) < 50 mL/min
• Inability to read/understand English

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: DOR/3TC/TDF; 100mg of doravirine (DOR), 300mg of lamivudine (3TC), and 300mg of tenofovir disoproxil fumarate (TDF)	Drug: DOR/3TC/TDF; switch antiretroviral regimen to doravirine/lamivudine/tenofovir disoproxil fumarate once daily for 1 year; Other Names: Delstrigo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify number of active clinic patients who meet eligibility criteria, and of those approached, how many accepted enrollment and completed the study protocol.	Feasibility (number eligible, enrolled and completed study)	1 year
Identify reasons for study ineligibility among clinic patients on INSTI-containing regimen who have experienced weight gain.	Descriptive data. Reasons for study ineligibility (i.e., not meeting inclusion criteria or presence of one or more exclusion criteria) will be recorded by the study coordinator.	1 year
Identify reasons for study refusal among clinic patients on INSTI-containing regimen who have experienced weight gain.	Descriptive data. Clinic patients who refuse to participate in the study will be asked an open-ended question by the study coordinator about main reason(s) for declining. Responses will be grouped by the following categories: fear of side effects, distrust of researchers, general concerns about research design, interference in everyday life or changes in routine, and social discrimination. These were main barriers to study participation identified in a meta-analysis by Mills et al. 2006 (PMID 16377532)	1 year
Identify factors associated with early study discontinuation.	Factors will include age, gender, race, CD4 count, HIV viral load, prior enrollment in a study, history of injection drug use, and use of antidepressants. These are variables which have previously been associated with early study discontinuation in a meta-analysis by Andersen et al (2007). PMID 17395549.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the change in absolute weight from baseline to one year following the switch from the INSTI-containing regimen to DOR/TDF/3TC.	Absolute weight (kg) - participants will be asked to remove heavy outer clothing, purses, footwear and heavy accessories or pocket contents.	1 year
To determine the change in relative weight change per year (i.e. weight trajectory) from baseline to one year following the switch from the INSTI-containing regimen to DOR/TDF/3TC.	Change in weight trajectory (change in weight - baseline vs 1 year prior to baseline compared to change in weight - week 48 versus baseline) in kg	1 year
To determine the change in waist circumference (cm) from baseline to one year following the switch from the INSTI-containing regimen to DOR/TDF/3TC.	Waist circumference to be measured using a landmark just above the uppermost lateral border of the right ilium (under the participant's clothing). Measurement will be recorded to the nearest tenth of a centimeter at the end of the participant's normal expiration.	1 year
To determine the change in BMI category from baseline to one year following the switch from the INSTI-containing regimen to DOR/TDF/3TC.	Change in BMI category: underweight (BMI<18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25-29.9), and obese (BMI 30 or more)	1 year
To determine the proportion of participants who maintain viral suppression (HIV RNA < 50 copies/ml) after a switch to DOR/TDF/3TC.	HIV RNA<50 copies/mL using Abbott RealTime HIV-1 assay.	1 year
Number of patients with treatment-related adverse events as assessed by the US DHHS NIH/NIAID Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, corrected version 2.1 (July 2017)	Adverse event parameters graded according to severity: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (potentially life-threatening), Grade 5 (death).	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the impact from baseline to one year following the switch from the INSTI-containing regimen to DOR/TDF/3TC on DXA body scans.	body composition (proportion of lean versus fat mass)	1 year
To determine the impact from baseline to one year following the switch from the INSTI-containing regimen to DOR/TDF/3TC on self-esteem related to body image as per the body image questionnaire B-WISE.	Body weight, image and self-esteem (B-WISE) evaluation questionnaire includes 12 items, each scored as 1 (never), 2 (sometimes) or 3 (all the time); a higher total score is indicative of better adjustment. ie., 12-20 = mild psychosocial impact, 21-28 = moderate psychosocial impact, 29-36 = severe psychosocial impact.	1 year
To determine the impact from baseline to one year following the switch from the INSTI-containing regimen to DOR/TDF/3TC on perceived changes in body size as per the FRAM body image questionnaire.	The fat redistribution and metabolic change (FRAM) questionnaire includes 7 areas of the body that the participant is asked to indicate noticed changes in size over the past year. Any changes are ranked from 1 (severely increased) to 6 (severely decreased). A lower total score indicates greater perceived increases in body size.	1 year
To determine the impact from baseline to one year following the switch from the INSTI-containing regimen to DOR/TDF/3TC on fasting glucose values.	fasting blood glucose (mmol/L), range 3.8-6.9.	1 year
To determine the impact from baseline to one year following the switch from the INSTI-containing regimen to DOR/TDF/3TC on insulin resistance (HOMA-IR).	HOMA score: fasting plasma glucose (mmol/L) times fasting serum insulin (mU/L) divided by 22.5. A score of <3 indicates normal insulin resistance, a score between 3 and -5 indicates moderate insulin resistance, and a score >5 indicates severe insulin resistance.	1 year
To determine the impact from baseline to one year following the switch from the INSTI-containing regimen to DOR/TDF/3TC on lipid values (standard lipid panel).	Standard lipid panel includes total cholesterol, HDL, LDL, triglycerides (all mmol/L) and total cholesterol:HDL ratio	1 year

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Collaborators: Merck Canada Inc.
• Investigators: Principal Investigator: Sharon Walmsley, University Health Network, Toronto

Publications and helpful links

General Publications

• Lakey W, Yang LY, Yancy W, Chow SC, Hicks C. Short communication: from wasting to obesity: initial antiretroviral therapy and weight gain in HIV-infected persons. AIDS Res Hum Retroviruses. 2013 Mar;29(3):435-40. doi: 10.1089/aid.2012.0234. Epub 2012 Nov 7.
• Kumar S, Samaras K. The Impact of Weight Gain During HIV Treatment on Risk of Pre-diabetes, Diabetes Mellitus, Cardiovascular Disease, and Mortality. Front Endocrinol (Lausanne). 2018 Nov 27;9:705. doi: 10.3389/fendo.2018.00705. eCollection 2018.
• 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.
• Gomez M, Seybold U, Roider J, Harter G, Bogner JR. Correction to: A retrospective analysis of weight changes in HIV-positive patients switching from a tenofovir disoproxil fumarate (TDF)- to a tenofovir alafenamide fumarate (TAF)-containing treatment regimen in one German university hospital in 2015-2017. Infection. 2019 Feb;47(1):103-104. doi: 10.1007/s15010-018-1251-0.
• Reynes J, Trinh R, Pulido F, Soto-Malave R, Gathe J, Qaqish R, Tian M, Fredrick L, Podsadecki T, Norton M, Nilius A. Lopinavir/ritonavir combined with raltegravir or tenofovir/emtricitabine in antiretroviral-naive subjects: 96-week results of the PROGRESS study. AIDS Res Hum Retroviruses. 2013 Feb;29(2):256-65. doi: 10.1089/aid.2011.0275. Epub 2012 Aug 3.
• Rockstroh JK, Lennox JL, Dejesus E, Saag MS, Lazzarin A, Wan H, Walker ML, Xu X, Zhao J, Teppler H, Dinubile MJ, Rodgers AJ, Nguyen BY, Leavitt R, Sklar P; STARTMRK Investigators. Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clin Infect Dis. 2011 Oct;53(8):807-16. doi: 10.1093/cid/cir510.
• McCann K, Moorhouse M, Sokhela S, Venter WD, Serenata C, Qavi A, et al. Changes in DXA-assessed body composition in TAF/FTC+DTG compared to TDF/FTC+DTG and TDF/FTC/EFV in the ADVANCE clinical trial. EACS, November 6-9, 2019, Basel, Switzerland.
• Bedimo R, Li X, Adams-Huet B, Lake J, Taylor B, Kim D, et al. Differential BMI changes following PI- and INSTI-based ART initiation by sex and race. Conference on Retroviruses and Opportunistic Infections; 2019 Mar 4-7; Seattle, Washington
• Rebeiro P, Jenkins C, Bian A, Lake J, Bourgi K, Horberg M, et al. The effect of initiating integrase inhibitor-based vs. non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy on progression to diabetes among North American persons in HIV care. IDWeek, October 2-6, 2019, Washington, DC. Abstract LB9.
• Schafer J, Sassa K, O'Connor J, Shimada A, Keith S, DeSimone J. BMI and ASCVD risk score changes in virologically suppressed patients with HIV switching from TDF to TAF containing ART. IDWeek, October 2-6, 2019, Washington, DC. Abstract 979
• Kerchberger AM, Sheth AN, Angert CD, Mehta CC, Summers NA, Ofotokun I, Gustafson D, Weiser SD, Sharma A, Adimora AA, French AL, Augenbraun M, Cocohoba J, Kassaye S, Bolivar H, Govindarajulu U, Konkle-Parker D, Golub ET, Lahiri CD. Weight Gain Associated With Integrase Stand Transfer Inhibitor Use in Women. Clin Infect Dis. 2020 Jul 27;71(3):593-600. doi: 10.1093/cid/ciz853.
• Johnson M, Kumar P, Molina JM, Rizzardini G, Cahn P, Bickel M, Mallolas J, Zhou Y, Morais C, Kumar S, Sklar P, Hanna GJ, Hwang C, Greaves W; DRIVE-SHIFT Study Group. Switching to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) Maintains HIV-1 Virologic Suppression Through 48 Weeks: Results of the DRIVE-SHIFT Trial. J Acquir Immune Defic Syndr. 2019 Aug 1;81(4):463-472. doi: 10.1097/QAI.0000000000002056.
• Hill A, Hughes SL, Gotham D, Pozniak AL. Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety? J Virus Erad. 2018 Apr 1;4(2):72-79.
• Andersen JW, Fass R, van der Horst C. Factors associated with early study discontinuation in AACTG studies, DACS 200. Contemp Clin Trials. 2007 Sep;28(5):583-92. doi: 10.1016/j.cct.2007.02.002. Epub 2007 Feb 27.
• Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed [October 30, 2019].

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 26, 2021
• Primary Completion (ANTICIPATED): August 1, 2024
• Study Completion (ANTICIPATED): December 31, 2024

Study Registration Dates

• First Submitted: November 24, 2020
• First Submitted That Met QC Criteria: December 10, 2020
• First Posted (ACTUAL): December 11, 2020

Study Record Updates

• Last Update Posted (ACTUAL): May 23, 2022
• Last Update Submitted That Met QC Criteria: May 17, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: HIV; tenofovir disoproxil fumarate; tenofovir alafenamide; integrase inhibitor; weight gain; doravirine
• Additional Relevant MeSH Terms: Body Weight Changes; Body Weight; Weight Gain
• Other Study ID Numbers: 20-5528

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
• product manufactured in and exported from the U.S.: No