Doravirine for Obese Persons on Integrase Inhibitors and Tenofovir Alafenamide

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections147 enrolled

Overview

The purpose of this study was to determine if people with HIV and obesity taking an antiretroviral treatment regimen containing an integrase strand transfer inhibitor (INSTI) with (tenofovir alafenamide/emtricitabine (TAF/FTC) would either slow their rate of weight gain, or even lose weight, over the span of about 1 year after a switch to a regimen containing doravirine (DOR; a newer, non-nucleoside reverse transcriptase inhibitor medication) combined with either TAF/TFC or tenofovir disoproxil fumarate (TDF)/FTC.

The study evaluated whether a switch from an INSTI to a DOR-based regimen would result in less weight gain or weight loss at 48 weeks among obese individuals with HIV and a suppressed viral load. The study also evaluated whether an additional switch from TAF/FTC to TDF/FTC, both in combination with DOR, had an effect on weight over 48 weeks. Participants enrolled in A5391 were taking INSTI-class medications, including bictegravir (BIC), dolutegravir (DTG), or raltegravir (RAL), all in combination with TAF/FTC. Additionally, the study examined whether a change in the HIV treatment regimen affects other health indicators, including waist circumference, metabolic and cardiovascular disease markers, body composition (fat and lean mass), bone density, and maintenance of virologic suppression. Finally, the study looked at the safety and tolerability of DOR with either TAF/FTC or TDF/FTC. As originally designed, the trial's target population included individuals with an unintentional \>10% weight gain in the 1-3 years after initiating or switching to an INSTI-based treatment regimen. Due to not meeting accrual targets during the first year of enrollment (July 2021 - July 2022), the trial protocol was updated to amend the target population (and associated eligibility criteria) to individuals with obesity (a screening body mass index \[BMI\] of ≥30 kg/m2) irrespective of weight history on INSTI-based ART. This update was implemented on November 17, 2022, at which time 64 participants had enrolled under the original trial design. The remaining participants enrolled using the revised eligibility criterion. At a planned interim analysis in 2023, the method of blinded sample size re-estimation was used to assess if the trial's primary objective could be met with a sample size smaller than originally planned (n=222). Based on the pooled (e.g. over all arms) standard deviation of the primary outcome (weight change at 48 weeks), 150 participants would provide over 80% statistical power to detect the originally hypothesized 5% points change in weight between arms, assuming that this interim estimate was representative of the true variability about the primary outcome. As a result, the accrual goal was adjusted accordingly. The trial closed to enrollment in October 2024, having reached 147 participants.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: Ability and willingness of participant or legal guardian/representative to provide informed consent. HIV-1, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, or plasma HIV-1 RNA viral load. If a rapid HIV test or any FDA-approved HIV-1 E/CIA test kit is not available, two HIV-1 RNA values ≥2000 copies/mL at least 24 hours apart may be performed by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or by any non-US laboratory that is DAIDS Good Clinical Laboratory Practice (GCLP) compliant and, if performing HIV-1 RNA testing, is Virology Quality Assurance (VQA)-certified. Currently on a bictegravir (BIC), dolutegravir (DTG), or raltegravir (RAL) + TAF/FTC regimen with ≥48 weeks prior to study entry. Ability to acquire NRTIs (TAF/FTC or TDF/FTC) and INSTI through usual care for the duration of the study. A BMI ≥30 kg/m2 at screening. No known plans to change or to initiate medications known to be associated with significant weight changes during study period. Agree to adhere to assigned ART during the study period At least one HIV-1 RNA level \<50 copies/mL (or below the lower limit of HIV-1 RNA detection available at the site if the lower limit of detection is \>50) performed in the 48 weeks prior (≤48 weeks) to study screening, and at least one HIV-1 RNA level \<50 copies/mL ≥48 weeks prior to study screening, using an FDA-approved assay performed by any US laboratory that has a CLIA certification or its equivalent, or at any network-approved non-US laboratory that is VQA certified. Screening HIV-1 RNA \<50 copies/mL (or below the lower limit of HIV-1 RNA detection available if the lower limit of detection is \>50) performed within 45 days prior to study entry by any US laboratory that possesses a CLIA certification or its equivalent, or at any network-approved non-US laboratory that is VQA certified. For participants capable of becoming pregnant, negative serum or urine pregnancy test within 45 days prior to study entry by any US clinic or laboratory that has a CLIA certification or its equivalent, or is using a point of care (POC)/ CLIA-waived test, or at any network-approved non-US laboratory or clinic that operates in accordance with GCLP and participates in appropriate external quality assurance programs. Participants engaging in sexual activity and capable of becoming pregnant must agree to use contraception while on study drug (approximately 48 weeks) and for 8 weeks after the end of the study. At least one of the following contraceptive methods must be used: * Intrauterine device (IUD) * Hormone-based contraceptive * Partner sterilization (i.e., vasectomy) and is the sole partner for the participant. Transgender participants who are currently taking hormones must be on a stable hormone dose for \>12 weeks prior to study entry. Transgender participants should not have active plans to change their hormone regimen or dose during the study period. The following laboratory values obtained within 45 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent, or at any network-approved non-US laboratory that operates in accordance with GCLP and participates in appropriate external quality assurance programs: * Absolute neutrophil count (ANC) \>750 cells/mm3 * Hemoglobin \>10 g/dL for males and \>9 g/dL for females (based on sex at birth) * Calculated creatinine clearance ≥50 mL/min as estimated by the CKD-EPI equation (a calculator is available at: https://qxmd.com/calculate/calculator\_251/egfr-using-ckd-epi) * Aspartate aminotransferase (AST) (SGOT) \<3x ULN * Alanine aminotransferase (ALT) (SGPT) \<3x ULN Exclusion Criteria: Historical or current evidence of the K65R/E/N or M184V/I mutations (for participants who have undergone HIV-1 genotyping), due to the potential for viral rebound after switch from an INSTI- to NNRTI-based regimen. Historical or current evidence of major mutations associated with NNRTI resistance. History of prior virologic failure in the opinion of the site investigator. For example, a confirmed plasma HIV-1 RNA \>1000 copies/mL after having achieved viral suppression. Prior exposure to single-dose nevirapine for the prevention of parent-to-child transmission of HIV. Any history of significant renal toxicity while taking TDF (as determined by the site investigator). Currently breast-feeding or pregnant, or intending to become pregnant during the duration of the study. Current use, use in the 4 weeks preceding study entry, or anticipated use of prohibited drugs during the study period. Anticipated start or cessation of any of the following drugs during the study period: * Antipsychotics (e.g., clozapine, olanzapine, risperidone, etc.) and antidepressants (tricyclic antidepressants, e.g., amitriptyline, nortriptyline, etc.; selective serotonin reuptake inhibitors, e.g., fluoxetine, paroxetine, sertraline, etc.; and monoamine oxidase inhibitors, e.g., selegiline) associated with weight gain * Anticonvulsants/mood stabilizers associated with weight gain (e.g., lithium, valproic acid) or weight loss (e.g., topiramate) * Thyroid replacement hormones * Anti-diabetic agents known to cause weight loss (e.g., GLP-1 receptor agonists such as exenatide, dulaglutide, semaglutide, metformin, and SGLT-2 inhibitors such as canagliflozin, dapagliflozin, etc.). Planning to undergo bariatric surgery or initiate significant dietary or exercise changes within the study period (e.g., structured weight loss programs such as Weight Watchers), as determined by participant report. Known allergy/sensitivity or any hypersensitivity to components of study drug or its formulation. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with ability to adhere to study requirements, or cessation of regular methamphetamine use, as determined by the site investigator, within 60 days prior to study entry. Acute or serious illness requiring systemic treatment and/or hospitalization within 30 days prior to entry. A history of a diagnosis of osteoporosis or osteopenia.

Outcomes

Primary Outcomes

Mean Change (Percent) in Body Weight (kg) From Entry to Week 48

The percentage change is defined as weight at week 48 minus weight at entry, then divided by weight at entry, then multiplied by 100. Mean and confidence interval (CI) come from a linear regression model adjusting for entry weight, sex, and race (Black and not Black).

Time frame: Entry to week 48

Secondary Outcomes

Mean Change (Percent) in Body Weight (kg) From Entry to Week 24

The percentage change is defined as weight at week 24 minus weight at entry, then divided by weight at entry, then multiplied by 100. Mean and CI come from a linear regression model adjusting for entry weight, sex, and race (Black and not Black).

Time frame: Entry to week 24

Mean Change (Absolute) in Waist Circumference From Entry to Week 48

The absolute change is defined as waist circumference at week 48 minus waist circumference at entry. Mean and CI come from a linear regression model adjusting for entry waist circumference, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Absolute) in Waist Circumference From Entry to Week 24

The absolute change is defined as waist circumference at week 24 minus waist circumference at entry. Mean and CI come from a linear regression model adjusting for entry waist circumference, sex, and race (Black and not Black).

Time frame: Entry to week 24

Mean Change (Absolute) in Fasting Triglycerides From Entry to Week 48

The absolute change is defined as triglycerides at week 48 minus triglycerides at entry. Mean and CI come from a linear regression model adjusting for entry triglycerides, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Absolute) in Fasting Triglycerides From Entry to Week 24

The absolute change is defined as triglycerides at week 24minus triglycerides at entry. Mean and CI come from a linear regression model adjusting for entry triglycerides, sex, and race (Black and not Black).

Time frame: Entry to week 24

Mean Change (Absolute) in Fasting Low-density Lipoprotein (LDL) Cholesterol From Entry to Week 48

The absolute change is defined as LDL at week 48 minus LDL at entry. Mean and CI come from a linear regression model adjusting for entry LDL, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Absolute) in Fasting Low-density Lipoprotein (LDL) Cholesterol From Entry to Week 24

The absolute change is defined as LDL at week 24 minus LDL at entry. Mean and CI come from a linear regression model adjusting for entry LDL, sex, and race (Black and not Black).

Time frame: Entry to week 24

Mean Change (Absolute) in Fasting High-density Lipoprotein (HDL) Cholesterol From Entry to Week 48

The absolute change is defined as HDL at week 48 minus HDL at entry. Mean and CI come from a linear regression model adjusting for entry HDL, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Absolute) in Fasting High-density Lipoprotein (HDL) Cholesterol From Entry to Week 24

The absolute change is defined as HDL at week 24 minus HDL at entry. Mean and CI come from a linear regression model adjusting for entry HDL, sex, and race (Black and not Black).

Time frame: Entry to week 24

Mean Change (Absolute) in Fasting Glucose From Entry to Week 48

The absolute change is defined as glucose at week 48 minus glucose at entry. Mean and CI come from a linear regression model adjusting for entry glucose, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Absolute) in Fasting Glucose From Entry to Week 24

The absolute change is defined as glucose at week 24 minus glucose at entry. Mean and CI come from a linear regression model adjusting for entry glucose, sex, and race (Black and not Black).

Time frame: Entry to week 24

Mean Change (Absolute) in Fasting Insulin From Entry to Week 48

The absolute change is defined as insulin at week 48 minus insulin at entry. Mean and CI come from a linear regression model adjusting for entry insulin, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Absolute) in Fasting Insulin From Entry to Week 24

The absolute change is defined as insulin at week 24 minus insulin at entry. Mean and CI come from a linear regression model adjusting for entry insulin, sex, and race (Black and not Black).

Time frame: Entry to week 24

Mean Change (Absolute) in Insulin Resistance (HOMA-IR) From Entry to Week 48

The absolute change is defined as HOMA-IR at week 48 minus HOMA-IR at entry. HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) is a method used to estimate how well the body responds to insulin and is calculated with the following formula: (Fasting insulin, μU/ml)\*(Fasting glucose, mg/dL) / 405 Mean and CI come from a linear regression model adjusting for entry HOMA-IR, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Absolute) in Insulin Resistance (HOMA-IR) From Entry to Week 24

The absolute change is defined as HOMA-IR at week 24 minus HOMA-IR at entry. HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) is a method used to estimate how well the body responds to insulin and is calculated with the following formula: (Fasting insulin, μU/ml)\*(Fasting glucose, mg/dL) / 405 Mean and CI come from a linear regression model adjusting for entry HOMA-IR, sex, and race (Black and not Black).

Time frame: Entry to week 24

Number of Participants With Confirmed Plasma HIV-1 RNA >200 Copies/mL

Number of participants with confirmed plasma HIV-1 RNA \>200 copies/mL, defined as two consecutive results above 200 copies, with the drawing of the second specimen within 2 weeks of site receipt of the first result, and the first result being from a specimen drawn after treatment initiation.

Time frame: Entry through week 48

Proportion of Participants With Grade ≥3 AEs From Entry to Week 48

Proportion of participants with Grade ≥3 AEs Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death.

Time frame: Entry to week 48

Proportion of Participants With >10% Reduction in Creatinine Clearance (CrCl) From Entry to Week 48

CrCl was estimated by the 2021 CKD-EPI equation and was measured at entry, week 4, week 12, week 24, and week 48. The percentage change is defined as CrCl at an on study visit minus CrCl at entry, then divided by CrCl at entry, then multiplied by 100. Participants were categorized as experiencing a \>10% reduction in CrCl if they experienced the \>10% reduction at any of the study visits (week 4, week 12, week 24, and week 48).

Time frame: Entry to week 48

Proportion of Participants With Premature Discontinuation of Study Treatment

Proportion of participants who permanently discontinued any component of study treatment prior to completion of a week 48 visit following randomization

Time frame: Entry to week 48

Mean Change (Percent) in Total Fat (kg) From Entry to Week 48

Total fat was measured by DEXA (dual-energy x-ray absorptiometry) scan. The percentage change is defined as total fat at week 48 minus total fat at entry, then divided by total fat at entry, then multiplied by 100. Mean and CI come from a linear regression model adjusting for entry total fat, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Percent) in Lean Mass (kg) From Entry to Week 48

Lean mass was measured by DEXA (dual-energy x-ray absorptiometry) scan. The percentage change is defined as lean mass at week 48 minus lean mass at entry, then divided by lean mass at entry, then multiplied by 100. Mean and CI come from a linear regression model adjusting for entry lean mass, sex, and race (Black and not Black).

Time frame: Day 0 to week 48

Mean Change (Percent) in Trunk Fat (kg) From Entry to Week 48

Trunk fat was measured by DEXA (dual-energy x-ray absorptiometry) scan. The percentage change is defined as trunk fat at week 48 minus trunk fat at entry, then divided by trunk fat at entry, then multiplied by 100. Mean and CI come from a linear regression model adjusting for entry trunk fat, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Percent) in Limb Fat (kg) From Entry to Week 48

Limb fat was measured by DEXA (dual-energy x-ray absorptiometry) scan. The percentage change is defined as limb fat at week 48 minus limb fat at entry, then divided by limb fat at entry, then multiplied by 100. Mean and CI come from a linear regression model adjusting for entry total fat, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Percent) in Appendicular Lean Mass (kg) From Entry to Week 48

Appendicular lean mass was measured by DEXA (dual-energy x-ray absorptiometry) scan. The percentage change is defined as appendicular lean mass at week 48 minus appendicular lean mass at entry, then divided by appendicular lean mass at entry, then multiplied by 100. Mean and CI come from a linear regression model adjusting for entry appendicular lean mass, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Percent) in Hip Bone Mineral Density (g/cm2) From Entry to Week 48

Hip bone mineral density was measured by DEXA (dual-energy x-ray absorptiometry) scan. The percentage change is defined as hip bone mineral density at week 48 minus hip bone mineral density at entry, then divided by hip bone mineral density at entry, then multiplied by 100. Mean and CI come from a linear regression model adjusting for entry hip bone mineral density, sex, and race (Black and not Black).

Time frame: Entry to week 48

Mean Change (Percent) in Lumbar Spine Bone Mineral Density (g/cm2) From Entry to Week 48

Lumbar spine bone mineral density was measured by DEXA (dual-energy x-ray absorptiometry) scan. The percentage change is defined as lumbar spine bone mineral density at week 48 minus lumbar spine bone mineral density at entry, then divided by lumbar spine bone mineral density at entry, then multiplied by 100. Mean and CI come from a linear regression model adjusting for entry lumbar spine bone mineral density, sex, and race (Black and not Black).

Time frame: Entry to week 48

Doravirine for Obese Persons on Integrase Inhibitors and Tenofovir Alafenamide

Overview

Conditions

Interventions

Eligibility

Locations (27)

Outcomes

Primary Outcomes

Secondary Outcomes