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

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)

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04665375

Acronym

DeLiTE

Enrollment

Registered

2020-12-11

Start date

2021-04-26

Completion date

2024-03-31

Last updated

2025-07-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hiv, Weight Gain

Keywords

weight gain, HIV, doravirine, integrase inhibitor, tenofovir alafenamide, tenofovir disoproxil fumarate

Brief summary

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.

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.

Interventions

DRUGDOR/3TC/TDF

switch antiretroviral regimen to doravirine/lamivudine/tenofovir disoproxil fumarate once daily for 1 year

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

Pilot intervention study

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Identify Number of Active Clinic Patients Who Completed the Study Protocol.	1 year	The primary objective was to determine how many clinic patients with ≥10% weight gain on an INSTI would complete the study (48 weeks).
Identify Factors Associated With Early Study Discontinuation.	1 year	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.
Identify Reasons for Study Refusal Among Clinic Patients on INSTI-containing Regimen Who Have Experienced Weight Gain.	1 year	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.
Identify Reasons for Study Ineligibility Among Clinic Patients on INSTI-containing Regimen Who Have Experienced Weight Gain.	1 year	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.

Secondary

Measure	Time frame	Description
Change in Waist Circumference From Baseline to One Year Following the Switch to DOR/TDF/3TC.	1 year	Change in waist circumference (value at 1 year minus value at baseline) will be reported. 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.
To Determine the Change in Absolute Weight From Baseline to One Year Following the Switch to DOR/TDF/3TC.	1 year	Absolute weight (kg) at one year minus weight at baseline (kg).
Number of Participants Who Experienced a Change in Weight After a Switch to DOR/TDF/3TC at 1 Year	1 year	To determine the number of participants who experienced either an increase, decrease or no change in weight (weight at 1 year vs. weight at baseline) following the switch to DOR/TDF/3TC.
Number of Participants Who Experienced a Change in BMI Category After a Switch to DOR/TDF/3TC at One Year	1 year	Number of participants with a change in BMI category (BMI category at one year compared to BMI category at baseline) following the switch to DOR/TDF/3TC.
Number of Participants Who Maintain HIV RNA<50 Copies/mL After a Switch to DOR/TDF/3TC at 1 Year	1 year	To determine the number of participants who maintain viral suppression (HIV RNA \< 50 copies/ml using Abbott RealTime HIV-1 assay) at 1 year after a switch to DOR/TDF/3TC.
Number of Patients With Treatment-related Adverse Events	1 year	Adverse event parameters graded according to severity: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (potentially life-threatening), Grade 5 (death) 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)

Other

Measure	Time frame	Description
To Determine the Change in Perceived Changes in Body Size as Per the FRAM Body Image Questionnaire	1 year	The change in FRAM scores (value at one year minus baseline value) will be measured.
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).	1 year	Standard lipid panel includes total cholesterol, HDL, LDL, triglycerides (all mmol/L) and total cholesterol:HDL ratio
Change in Self-esteem Related to Body Image as Per the Body Image Questionnaire B-WISE at One Year Versus Baseline.	1 year	The Body Weight, Image and Self-Esteem (B-WISE) questionnaire is a validated 12-item, self-administered questionnaire that assesses body image and self-esteem related to weight gain. It was selected to assess impact of weight gain/change in our study. B-WISE scores range between 12-36; higher scores are indicative of better psychosocial adjustment (12-20 = severe; 21-28 = moderate; 29-36 = mild). The change in total B-WISE scores (value at one year minus value at baseline) will be calculated.
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).	1 year	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.
Loss of Percentage of Total Body Fat From Baseline to One Year	1 year	loss of percentage of total body fat (difference at one year minus from baseline) following the switch from the INSTI-containing regimen to DOR/TDF/3TC according to DXA body scans.
Change in Fasting Glucose Values Following the Switch From the INSTI-containing Regimen to DOR/TDF/3TC	1 year	The change in fasting blood glucose (value at one year minus baseline value) will be measured.

Countries

Canada

Participant flow

Participants by arm

Arm	Count
DOR/3TC/TDF 100mg of doravirine (DOR), 300mg of lamivudine (3TC), and 300mg of tenofovir disoproxil fumarate (TDF) DOR/3TC/TDF: switch antiretroviral regimen to doravirine/lamivudine/tenofovir disoproxil fumarate once daily for 1 year	3
Total	3

Baseline characteristics

Characteristic	DOR/3TC/TDF
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	1 Participants
Age, Categorical Between 18 and 65 years	2 Participants
Age, Continuous	59 years
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	3 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	0 Participants
Region of Enrollment Canada	3 Participants
Sex: Female, Male Female	3 Participants
Sex: Female, Male Male	0 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 3
other Total, other adverse events	0 / 3
serious Total, serious adverse events	0 / 3

Outcome results

Primary

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.

Time frame: 1 year

Population: Participants who did not complete the study to week 48.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
DOR/3TC/TDF	Identify Factors Associated With Early Study Discontinuation.	study closed to futility	1 Participants
DOR/3TC/TDF	Identify Factors Associated With Early Study Discontinuation.	completed study to week 48	3 Participants

Primary

Identify Number of Active Clinic Patients Who Completed the Study Protocol.

The primary objective was to determine how many clinic patients with ≥10% weight gain on an INSTI would complete the study (48 weeks).

Time frame: 1 year

Population: Number of clinic patients who experienced ≥10% weight gain on an INSTI within the last 5 years.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
DOR/3TC/TDF	Identify Number of Active Clinic Patients Who Completed the Study Protocol.	3 Participants

Primary

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.

Time frame: 1 year

Population: Number of participants screened for the study.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
DOR/3TC/TDF	Identify Reasons for Study Ineligibility Among Clinic Patients on INSTI-containing Regimen Who Have Experienced Weight Gain.	started semaglutide	1 Participants
DOR/3TC/TDF	Identify Reasons for Study Ineligibility Among Clinic Patients on INSTI-containing Regimen Who Have Experienced Weight Gain.	did not meet weight gain threshold	1 Participants
DOR/3TC/TDF	Identify Reasons for Study Ineligibility Among Clinic Patients on INSTI-containing Regimen Who Have Experienced Weight Gain.	greater than 5 years INSTI use	1 Participants

Primary

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.

Time frame: 1 year

Population: Number of individuals who refused screening/participation in the study.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
DOR/3TC/TDF	Identify Reasons for Study Refusal Among Clinic Patients on INSTI-containing Regimen Who Have Experienced Weight Gain.	0 Participants

Secondary

Change in Waist Circumference From Baseline to One Year Following the Switch to DOR/TDF/3TC.

Change in waist circumference (value at 1 year minus value at baseline) will be reported. 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.

Time frame: 1 year