Effects of Switch to Doravirine/Islatravir vs. Continued Antiretroviral Therapy on Biomarkers of Aging Among Virologically Suppressed People With HIV

• Switch from an ART regimen containing lamivudine (3TC) or emtricitabine (FTC) + tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) to DOR/ISL (Drug): DOR/ISL (100mg/0.25mg) will be supplied as coformulated tablets to be taken orally once daily.
• Switch from an nucleoside reverse transcriptase inhibitor (NRTI)-sparing ART regimen containing greater than or equal to 2 drugs to DOR/ISL (Drug): DOR/ISL (100mg/0.25mg) will be supplied as coformulated tablets to be taken orally once daily.
• Continue SoC ART (Drug): participants will continue to receive standard of care ART

Primary outcomes

• Biologic aging, as measured by validated epigenetic clocks [Baseline]: Epigenetic age will be estimated using DNA methylation-based epigenetic clock analysis. Epigenetic age will be reported in years.
• Biologic aging, as measured by validated epigenetic clocks [Week 24]: Epigenetic age will be estimated using DNA methylation-based epigenetic clock analysis. Epigenetic age will be reported in years.
• Change in biologic aging, as measured by validated epigenetic clocks [Baseline, week 24]: Epigenetic age will be estimated using DNA methylation-based epigenetic clock analysis. Epigenetic age will be reported in years.

Secondary outcomes

• Change in epigenetic age in participants switching to DOR/ISL from a NRTI-sparing regimen vs. NRTI-containing regimen [Baseline, week 24]: Epigenetic age will be estimated using DNA methylation-based epigenetic clock analysis. Epigenetic age will be reported in years.
• Change in epigenetic age in participants switching to DOR/ISL from a NRTI-sparing regimen vs. SOC ART [Baseline, week 24]: Epigenetic age will be estimated using DNA methylation-based epigenetic clock analysis. Epigenetic age will be reported in years.
• Change in epigenetic age in participant switching to DOR/ISL from a NRTI-containing regimen vs. SOC ART [Baseline, week 24]: Epigenetic age will be estimated using DNA methylation-based epigenetic clock analysis. Epigenetic age will be reported in years.
• Change in pace of aging in participants switching to DOR/ISL from a NRTI-sparing regimen vs. NRTI-containing regimen [Baseline, week 24]: This will be estimated from DNA isolated from whole blood collected in a DNA/RNA Shield tube using DNA methylation-based epigenetic clock analysis.
• Change in pace of aging in participants switching to DOR/ISL from a NRTI-sparing regimen vs. SOC ART [Baseline, week 24]: This will be estimated from DNA isolated from whole blood collected in a DNA/RNA Shield tube using DNA methylation-based epigenetic clock analysis.
• Change in pace of aging in participants switching to DOR/ISL from a NRTI-containing regimen vs. SOC ART [Baseline, week 24]: This will be estimated from DNA isolated from whole blood collected in a DNA/RNA Shield tube using DNA methylation-based epigenetic clock analysis.
• Pace of aging in participants continuing SoC ART [from baseline to week 24]: This will be estimated from DNA isolated from whole blood collected in a DNA/RNA Shield tube using DNA methylation-based epigenetic clock analysis.
• Change in epigenetic age in participants continuing SoC ART [Baseline, week 24]: Epigenetic age will be estimated using DNA methylation-based epigenetic clock analysis. Epigenetic age will be measured in years.
• DOR/ISL tolerability as assessed by number of adverse events reported [from baseline to week 24]

Sex: All, ages: 35 Years to any

Inclusion Criteria:

* Living with HIV-1 and on ART for greater than or equal to 2 years (to allow for epigenetic stabilization after ART initiation
* Current ART greater than or equal to 6 months prior to entry. ART must contain 1) FTC or 3TC with TAF or TDF or 2) any NRTI-sparing regimen consisting of greater than or equal to 2 drugs
* HIV-1 RNA <50 copies/mL at screening and less than or equal to 200 copies/mL within 6 months of entry (latter according to clinical care records). Repeat HIV-1 RNA within the screening allowed if needed to verify eligibility.
* Able and willing to provide informed consent and undergo study procedures.

Exclusion Criteria:

* HIV-2
* Pregnant or nursing, or intent to become pregnant during the study period
* Hypersensitivity or other contraindication to DOR or ISL or any of the components of the study product, as determined by the site investigator.
* Active AIDS-defining opportunistic infection <30 days prior to entry.
* Active malignancy (exclusive of basal/squamous cell skin cancer)
* Active Hepatitis B Virus
* Chronic Hepatitis C Virus
* Other concomitant chronic inflammatory diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis), in the opinion of the site investigator
* Advanced liver disease (Childs-Pugh Class B or C)
* Any condition, therapy, laboratory abnormality or other circumstance that the site investigator feels may confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate.
* Concomitant (current or <45 days of entry) use of any investigational compound or device.
* Is taking or is anticipated to require systemic immunosuppressive therapy, immune modulators, or strong and moderate Cytochrome P450 3A (CYP3A) inducers from <45 days prior to entry through the study treatment period
* Documented or known virologic resistance to DOR, as demonstrated by any of the following DOR resistance substitutions in RT: Valine106Alanine/Methionine (V106A/M), Valine108 Isoleucine (V108I), tyrosine 188 leucine (Y188L), Histidine 221 tyrosine (H221Y), Proline 225 histidine (P225H), Phenylalanine 227 cysteine, leucine, or valine (F227C/L/V), Methionine 230 isoleucine/leucine (M230I/L), Leucine 2341 isoleucine (L234I), Proline 236 leucine (P236L) or Tyrosine 318 phenylalanine (Y318F)
* Concern for risk of virologic failure with switch to DOR, based on participant history and in the opinion of the site investigator
* Use of agents containing glucagon-like peptide-1 receptor agonists during the study or within 24 W of entry
* Any of the following laboratory abnormalities:
* Alkaline phosphatase (AP), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5x the upper limit of normal (ULN).
* Calculated creatinine clearance less than or equal to 30 mL/min, as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation -Cluster of Differentiation 4 (CD4+) T cell count <50 cells/mm3
* Absolute lymphocyte count <0.650 × 109 cells/L
* Hemoglobin (Hb) <9 or <10 g/dL for persons assigned female or male sex at birth, respectively

• Jordan E Lake, MD, MSc, Principal investigator, The University of Texas Health Science Center, Houston