A Study to Evaluate the Anti-inflammatory Effects of Letermovir (Prevymis) in Adults With Human Immunodeficiency Virus (HIV)-1 and Asymptomatic Cytomegalovirus (CMV) Who Are on Suppressive Antiretroviral Therapy, Plus Its Effect on Chronic Inflammation, HIV Persistence and Other Clinical Outcomes.

Inclusion Criteria:

1. HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme orchemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry andconfirmed by a licensed Western blot or a second antibody test by a method otherthan the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viralload.

• NOTE: The term "licensed" refers to a US FDA-approved kit, which is requiredfor all IND studies. WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention)guidelines mandate that confirmation of the initial test result must use a test thatis different from the one used for the initial assessment. More information on thiscriterion can be found in the protocol.

2. Currently on continuous combination ART (antiretroviral therapy) for ≥48 weeks priorto study entry. This is defined as continuous ART for the 48-week period prior tostudy entry with no ART interruption longer than 7 consecutive days.

3. Screening plasma HIV-1 RNA <40 copies/mL within 90 days prior to study entry using aFDA-approved assay with a quantification limit of 40 copies/mL or lower performed byany US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA)certification or its equivalent.

4. HIV-1 RNA level <40 copies/mL for at least 48 weeks prior to study entry performedby any US laboratory that has a CLIA certification or its equivalent.

• NOTE: Single determinations that are between the assay quantification limit and 500 copies/mL (i.e., "blips") are allowed as long as the preceding andsubsequent determinations are below the level of quantification. The screeningvalue may serve as the subsequent undetectable value following a blip.

5. CD4⁺/CD8⁺ cell count obtained within 90 days prior to study entry at any USlaboratory that has a CLIA certification or its equivalent.

6. Positive CMV IgG serology, at any time prior to study entry using a FDA-approvedassay at any US laboratory that has a CLIA certification or its equivalent.

• NOTE: If a prior positive CMV IgG serology test is confirmed in the medicalrecord, a repeat CMV IgG test is not required at screening.

7. The following laboratory values obtained within 90 days prior to study entry by anyUS laboratory that has a CLIA certification or its equivalent:

• Hemoglobin >9.0 g/dL

• Platelet count >75,000/mm³

• Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) (SGPT),and alkaline phosphatase ≤3 x ULN (upper limit of normal)

• Total bilirubin ≤2.5 x ULN

• NOTE: If an individual is taking atazanavir-containing regimen at the timeof screening, a total bilirubin of ≤5 x ULN is acceptable.

• Estimated Glomerular Filtration Rate (eGFR) >30 mL/min/1.73m² or creatinineclearance (CrCl) >30 mL/min using the Cockcroft-Gault, EPI-GFR or MDRDequations located on the DMC website.

8. For individuals assigned female sex at birth and of reproductive potential, negativeserum or urine pregnancy test within 24 hours prior to study entry by any US clinicor laboratory that has a CLIA certification or its equivalent, or a CLIA Certificateof Waiver for those performing a point of care (POC)/CLIA-waived test. (Urine testmust have a sensitivity of <25 mlU/mL).

• NOTE: Persons of female sex assigned at birth and of reproductive potential aredefined as having reached menarche and have not been post-menopausal for atleast 24 consecutive months (i.e. have had menses within the preceding 24months), and have not undergone testosterone therapy for gender alignment orsurgical sterilization such as hysterectomy, bilateral oophorectomy, tuballigation or salpingectomy. An individual's report is considered acceptabledocumentation or reproductive status.

9. All participants that are participating in sexual activity that could lead topregnancy must agree to use contraception throughout the study. At least one of thefollowing must be used throughout the study:

• Diaphragm or cervical cap with spermicide

• Intrauterine device (IUD)

• Hormone-based contraceptive

• Condoms with or without a spermicide

• NOTE A: Individuals who are not of reproductive potential are not requiredto use contraception.

• NOTE B: Sperm-producing participants should refrain from donating spermduring the treatment period and for at least 90 days after the last doseof study treatment.

10. Ability and willingness of individual or legal guardian/representative to provideinformed consent.

Exclusion Criteria:

1. Change in the ART regimen within 12 weeks prior to study entry or intendedmodification of ART during the study.

• NOTE: Modifications in the dosage or frequency (i.e. twice a day [bid] to oncea day [qd]) of individual antiretroviral (ARV) drugs during the 12 weeks priorto study entry are permitted. In addition, the change in formulation (e.g. fromstandard formulation to fixed-dose combination) is allowed within 12 weeksprior to study entry. A within class single drug substitution (e.g. switch fromatazanavir to darunavir, or tenofovir disoproxil fumarate to tenofoviralafenamide) is allowed within 12 weeks prior to study entry. A switch to anyother nucleoside reverse transcriptase inhibitor (NRTI) from abacavir (or viceversa) is not permissible. No other changes in ART within the 12 weeks prior tostudy entry are permitted.

2. Use of any of the following ARV drugs in current regimen: efavirenz, nevirapine,etravirine, lopinavir/ritonavir, and once-daily dosing of raltegravir (bid dosing ofraltegravir is acceptable).

3. Two or more HIV-1 RNA determinations >200 copies/mL within 48 weeks prior to studyentry.

4. Any febrile illness (>101°F) within 30 days prior to study entry.

5. Use of drugs with anti-CMV activity within 90 days prior to study entry, with theexception of standard dose valacyclovir and acyclovir. See the protocol for moreinformation.

6. Immunosuppressive or immunomodulatory drug use, with the exception of topical,inhaled, and intranasal corticosteroids within 90 days prior to study entry. See theprotocol for more information.

7. Concomitant use of prohibited medications. See the protocol for more information.

8. Persons who are breastfeeding, pregnant or planning to become pregnant during thestudy.

9. Participating in a study where co-enrollment is not allowed.

10. Receipt of any vaccination within 14 days prior to study entry.

11. Presence on screening ECG or a known history of atrial tachycardia (other than sinustachycardia). Ventricular tachycardia is also an exclusion criterion.

12. History of cardiomyopathy or congenital heart disease or evidence of advancedconduction system disease including second degree heart block Mobitz type II, thirddegree heart block, AV dissociation or ECG findings that may be suggestive ofpredisposition to arrhythmia (i.e. delta wave).

13. Known allergy/sensitivity or any hypersensitivity to components of the study drug orits formulation.

14. Active drug or alcohol use or dependence that, in the opinion of the siteinvestigator, would interfere with adherence to study requirements.

15. Acute or serious illness requiring systemic treatment and/or hospitalization within 90 days prior to study entry.

16. Known chronic active hepatitis B virus infection within the last 24 weeks prior tostudy entry.

• NOTE: Active is defined as hepatitis B surface antigen (HBsAg) positive andhepatitis B DNA (HBV DNA) positive. Persons with HBV DNA below level ofquantification (BLQ) for >24 weeks prior to study entry are eligible.

17. Known chronic active hepatitis C within the last 24 weeks prior to study entry.

• NOTE: Active is defined as a detectable plasma hepatitis C virus (HCV) RNAlevel. Persons with HCV RNA BLQ for >24 weeks prior to study entry areeligible.

18. Presence of history of conditions that could account for impaired neuropsychologicalperformance (if present), including head injury with prolonged (>1 hour) loss ofconsciousness, central nervous system infection (e.g. encephalitis), severe learningdisability, psychosis, and/or active drug or alcohol use, or dependence that, in theopinion of the site investigator, would interfere with adherence to studyrequirements.

19. History of multi-class HIV drug resistance or intolerance, such that in the opinionof the investigator, an alternative fully active antiretroviral regimen cannot beconstructed should the participant experience loss of viral suppression on theircurrent regimen during the study.