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

Phase 4

Terminated

Conditions: Hiv
Weight Gain

Interventions: Drug: DOR/3TC/TDF

Registration Number: NCT04665375

Lead Sponsor: University Health Network, Toronto

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 4

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
DOR/3TC/TDF	DOR/3TC/TDF	100mg of doravirine (DOR), 300mg of lamivudine (3TC), and 300mg of tenofovir disoproxil fumarate (TDF)

Primary Outcome Measures

Name	Time	Method
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 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.
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 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.

Secondary Outcome Measures

Name	Time	Method
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 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)
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.
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.