Overview

The primary purpose of this study is to see if people with HIV who had a significant weight gain after starting INSTI (integrase strand transfer inhibitor)+TAF/FTC (tenofovir alafenamide/emtricitabine) (TAF/3TC (lamivudine)) regimen could either slow their rate of weight gain or lose weight within about 1 year if they switch to a regimen containing doravirine (DOR; a newer, non-nucleoside reverse transcriptase inhibitor medication). The study will also try to see if participants changing from TAF/FTC (or TAF/3TC) to TDF/FTC (or TDF/3TC) will experience less additional weight gain or a reduction in overall body weight at 48 weeks compared to persons continued on an INSTI + TAF/FTC (or TAF/3TC) combination. INSTINs assessed in A5391 include bictegravir (BIC), dolutegravir (DTG), or raltegravir (RAL). Additionally, the study will see whether a change in ART can affect things like waist circumference, metabolic and cardiovascular health, fat and lean mass body composition, bone health, and maintenance of virologic suppression. Finally, the study will look at the safety and tolerability of DOR plus either TAF/FTC (or TAF/3TC) versus TDF/FTC (or TDF/3TC).

Eligibility

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.

        NOTE: The term "licensed" refers to a US FDA-approved kit, or for sites located in
        countries other than the United States, a kit that has been certified or licensed by an
        oversight body within that country and validated internally.
        World Health Organization (WHO) and CDC (Centers for Disease Control and Prevention)
        guidelines mandate that confirmation of the initial test result must use a test that is
        different from the one used for the initial assessment. A reactive initial rapid test
        should be confirmed by either another type of rapid assay or an E/CIA that is based on a
        different antigen preparation and/or different test principle (e.g., indirect versus
        competitive), or a Western blot or a plasma HIV-1 RNA viral load.
          -  Currently, on a BIC (bictegravir), DTG (dolutegravir), or RAL (raltegravir) +TAF/FTC
             (or TAF/3TC) regimen with ≥48 weeks INSTI+TAF/FTC (or TAF/3TC) dosing prior to study
             entry.
        NOTE A: Participants who did not start TAF at the same time as they started an INSTI will
        be eligible if they started TAF/FTC (or TAF/3TC) ≥48 weeks prior to study entry.
        NOTE B: Participants who underwent within-INSTI class substitutions (including from EVG
        (elvitegravir) to BIC, DTG, or RAL) will be eligible if substitution occurred ≥24 weeks
        prior to study entry.
        NOTE C: Participants are permitted ART adherence gaps of ≤7 days (i.e., missed doses), with
        a maximum of 3 gaps in the 48 weeks prior to study entry.
          -  Ability to acquire NRTIs (TAF/FTC or TAF/3TC, and TDF/FTC or TDF/3TC) and INSTI
             through usual care for the duration of the study.
          -  A BMI ≥27.5 kg/m2 at screening.
          -  An unintentional >10% weight gain in the 1-3 years after initiating or switching to
             INSTI-based ART and with ≥48 weeks of TAF/FTC (or TAF/3TC) preceding enrollment, as
             ascertained from clinical records, with no other medically apparent reason to readily
             explain the weight gain (including, but not limited to, concomitant medication use
             [e.g., corticosteroids], Cushing's disease, recent prolonged hospitalization, etc.),
             in the opinion of the site investigator.
          -  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. HIV-1 RNA values prior
             to the screening visit will be assessed for eligibility by the site and assay dates
             and values do not need to be entered on an eCRF.
          -  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.
        NOTE: Participants capable of becoming pregnant are defined as individuals who were
        assigned a female sex at birth and of reproductive potential; (i.e., have reached menarche
        and who have not been post-menopausal for at least 24 consecutive months, and have not
        undergone surgical sterilization such as hysterectomy, bilateral oophorectomy, tubal
        ligation, or salpingectomy). This includes transgender men who could become pregnant if
        menstruation were not suppressed. Participant-reported history is acceptable documentation
        of menopause.
          -  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.
        NOTE: Participant report of partner sterilization is acceptable.
          -  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.
        NOTE: As some transgender participants may also use hormones purchased outside of the
        medical system (e.g., street hormones), the medication history should include questions
        about the use of these agents.
          -  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 any NNRTI
             resistance.
        NOTE: Refer to the IAS-USA 2019 mutations list, including significant substitutions at
        positions 100, 101, 103, 106, 138, 179, 181, 188, 190, 221, 225, 227, 230, or 234 [22].
          -  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 site
             investigator).
          -  Currently breast-feeding or pregnant, or intending to become pregnant during the
             duration of the study.
          -  Anticipated start or cessation of any of the following drugs during 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.).
        NOTE A: Participants currently receiving antipsychotics, antidepressants,
        anticonvulsants/mood stabilizers, and thyroid replacement hormones with no dose
        modifications for at least 12 weeks prior to entry are eligible.
        NOTE B: Participants currently receiving anti-diabetic agents known to cause weight loss
        with no dose modifications for at least 24 weeks prior to entry are eligible.
          -  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 routine methamphetamine use within 60 days prior to study entry.
        NOTE: Routine methamphetamine use is considered >4 days per week.
          -  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.