Doravirine for Persons with Excessive Weight Gain on Integrase Inhibitors and Tenofovir Alafenamide

Inclusion Criteria:

• Ability and willingness of participant or legal guardian/representative to provideinformed consent.

• HIV-1, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescenceimmunoassay (E/CIA) test kit at any time prior to study entry and confirmed by alicensed Western blot or a second antibody test by a method other than the initialrapid HIV and/or E/CIA, or by HIV-1 antigen, or plasma HIV-1 RNA viral load. If arapid HIV test or any FDA-approved HIV-1 E/CIA test kit is not available, two HIV-1RNA values ≥2000 copies/mL at least 24 hours apart may be performed by any USlaboratory that has a Clinical Laboratory Improvement Amendments (CLIA)certification or its equivalent, or by any non-US laboratory that is DAIDS GoodClinical 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 studyentry.

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 INSTIthrough 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 toINSTI-based ART and with ≥48 weeks of TAF/FTC (or TAF/3TC) preceding enrollment, asascertained from clinical records, with no other medically apparent reason toreadily explain the weight gain (including, but not limited to, concomitantmedication use [e.g., corticosteroids], Cushing's disease, recent prolongedhospitalization, etc.), in the opinion of the site investigator.

• No known plans to change or to initiate medications known to be associated withsignificant 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 RNAdetection available at the site if the lower limit of detection is >50) performed inthe 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 assayperformed by any US laboratory that has a CLIA certification or its equivalent, orat any network-approved non-US laboratory that is VQA certified. HIV-1 RNA valuesprior to the screening visit will be assessed for eligibility by the site and assaydates 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 detectionavailable if the lower limit of detection is >50) performed within 45 days prior tostudy entry by any US laboratory that possesses a CLIA certification or itsequivalent, or at any network-approved non-US laboratory that is VQA certified.

• For participants capable of becoming pregnant, negative serum or urine pregnancytest within 45 days prior to study entry by any US clinic or laboratory that has aCLIA certification or its equivalent, or is using a point of care (POC)/ CLIA-waivedtest, or at any network-approved non-US laboratory or clinic that operates inaccordance with GCLP and participates in appropriate external quality assuranceprograms.

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 agreeto use contraception while on study drug (approximately 48 weeks) and for 8 weeksafter the end of the study. At least one of the following contraceptive methods mustbe used:

• Intrauterine device (IUD)

• Hormone-based contraceptive

• Partner sterilization (i.e., vasectomy) and is the sole partner for theparticipant.

NOTE: Participant report of partner sterilization is acceptable.

• Transgender participants who are currently taking hormones must be on a stablehormone dose for >12 weeks prior to study entry. Transgender participants should nothave 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 anyUS laboratory that has a CLIA certification or its equivalent, or at anynetwork-approved non-US laboratory that operates in accordance with GCLP andparticipates 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 (forparticipants who have undergone HIV-1 genotyping), due to the potential for viralrebound after switch from an INSTI- to NNRTI-based regimen.

• Historical or current evidence of major mutations associated with any NNRTIresistance.

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. Forexample, a confirmed plasma HIV-1 RNA >1000 copies/mL after having achieved viralsuppression.

• Prior exposure to single-dose nevirapine for the prevention of parent-to-childtransmission of HIV.

• Any history of significant renal toxicity while taking TDF (as determined by siteinvestigator).

• Currently breast-feeding or pregnant, or intending to become pregnant during theduration of the study.

• Anticipated start or cessation of any of the following drugs during study period:

• Antipsychotics (e.g., clozapine, olanzapine, risperidone, etc.) andantidepressants (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 agonistssuch as exenatide, dulaglutide, semaglutide, metformin, and SGLT-2 inhibitorssuch 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 exercisechanges within the study period (e.g., structured weight loss programs such asWeight Watchers), as determined by participant report.

• Known allergy/sensitivity or any hypersensitivity to components of study drug or itsformulation.

• Active drug or alcohol use or dependence that, in the opinion of the siteinvestigator, would interfere with ability to adhere to study requirements, orcessation 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.