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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Hiv, Weight Gain

Intervention / Treatment
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* Drug: DOR/3TC/TDF


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Pilot intervention study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DOR/3TC/TDF<br>100mg of doravirine (DOR), 300mg of lamivudine (3TC), and 300mg of tenofovir disoproxil fumarate (TDF) | Drug: DOR/3TC/TDF<br>* switch antiretroviral regimen to doravirine/lamivudine/tenofovir disoproxil fumarate once daily for 1 year<br>* Other names: Delstrigo;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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weight gain, HIV, doravirine, integrase inhibitor, tenofovir alafenamide, tenofovir disoproxil fumarate