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.

Study Overview
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Brief Summary
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This is an open-label, controlled study, conducted at US sites to evaluate the anti-inflammatory effectiveness of the study drug letermovir in adults with HIV and asymptomatic cytomegalovirus (CMV) who are on antiretroviral therapy (ART)-mediated suppression. Participants will be randomly assigned to receive either letermovir once daily or no anti-CMV treatment, for 48 weeks.

Detailed Description
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This is a phase 2, randomized, open-label, controlled, multicenter trial to evaluate the anti-inflammatory efficacy of letermovir, administered once daily for 48 weeks in adults with HIV and asymptomatic CMV, who are on ART-mediated suppression. Participants will be randomized 1:1 to receive either letermovir or no anti-CMV treatment. A futility analysis will be performed after the first 40 participants to initiate study treatment reach their 8-week study visit. Study enrollment will be paused after the 40th participant starts treatment until the results of the futility analysis have been considered.

Official Title
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Randomized, Controlled Trial to Evaluate the Anti-inflammatory Efficacy of Letermovir (Prevymis) in Adults With Human Immunodeficiency Virus (HIV)-1 and Asymptomatic Cytomegalovirus (CMV) Who Are on Suppressive ART and Its Effect on Chronic Inflammation, HIV Persistence, and Other Clinical Outcomes

Conditions
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HIV Infections, Cytomegalovirus, CMV

Intervention / Treatment
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* Drug: Letermovir 240 MG Oral Tablet
* Drug: Letermovir 480 MG Oral Tablet
* Drug: Combination ART


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection, 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, plasma HIV-1 RNA viral load. NOTE: The term licensed refers to a US FDA-approved kit, which is required for 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 that is different from the one used for the initial assessment. More information on this criterion can be found in the protocol. Currently on continuous combination ART (antiretroviral therapy) for ≥48 weeks prior to study entry. This is defined as continuous ART for the 48-week period prior to study entry with no ART interruption longer than 7 consecutive days. Screening plasma HIV-1 RNA <40 copies/mL within 90 days prior to study entry using a FDA-approved assay with a quantification limit of 40 copies/mL or lower performed by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent. HIV-1 RNA level <40 copies/mL for at least 48 weeks prior to study entry performed by 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 and subsequent determinations are below the level of quantification. The screening value may serve as the subsequent undetectable value following a blip. CD4⁺/CD8⁺ cell count obtained within 90 days prior to study entry at any US laboratory that has a CLIA certification or its equivalent. Positive CMV IgG serology, at any time prior to study entry using a FDA-approved assay 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 medical record, a repeat CMV IgG test is not required at screening. The following laboratory values obtained within 90 days prior to study entry by any US 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 time of screening, a total bilirubin of ≤5 x ULN is acceptable. Estimated Glomerular Filtration Rate (eGFR) >30 mL/min/1.73m² or creatinine clearance (CrCl) >30 mL/min using the Cockcroft-Gault, EPI-GFR or MDRD equations located on the DMC website. For individuals assigned female sex at birth and of reproductive potential, negative serum or urine pregnancy test within 24 hours prior to study entry by any US clinic or laboratory that has a CLIA certification or its equivalent, or a CLIA Certificate of Waiver for those performing a point of care (POC)/CLIA-waived test. (Urine test must have a sensitivity of <25 mlU/mL). NOTE: Persons of female sex assigned at birth and of reproductive potential are defined as having reached menarche and have not been post-menopausal for at least 24 consecutive months (i.e. have had menses within the preceding 24 months), and have not undergone testosterone therapy for gender alignment or surgical sterilization such as hysterectomy, bilateral oophorectomy, tubal ligation or salpingectomy. An individual's report is considered acceptable documentation or reproductive status. All participants that are participating in sexual activity that could lead to pregnancy must agree to use contraception throughout the study. At least one of the following 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 required to use contraception. NOTE B: Sperm-producing participants should refrain from donating sperm during the treatment period and for at least 90 days after the last dose of study treatment. Persons age greater than or equal to 40 years. Ability and willingness of individual or legal guardian/representative to provide informed consent. Exclusion Criteria: Change in the ART regimen within 12 weeks prior to study entry or intended modification of ART during the study. NOTE: Modifications in the dosage or frequency (i.e. twice a day [bid] to once a day [qd]) of individual antiretroviral (ARV) drugs during the 12 weeks prior to study entry are permitted. In addition, the change in formulation (e.g. from standard formulation to fixed-dose combination) is allowed within 12 weeks prior to study entry. A within class single drug substitution (e.g. switch from atazanavir to darunavir, or tenofovir disoproxil fumarate to tenofovir alafenamide) is allowed within 12 weeks prior to study entry. A switch to any other nucleoside reverse transcriptase inhibitor (NRTI) from abacavir (or vice versa) is not permissible. No other changes in ART within the 12 weeks prior to study entry are permitted. Use of any of the following ARV drugs in current regimen: efavirenz, nevirapine, etravirine, lopinavir/ritonavir, and once-daily dosing of raltegravir (bid dosing of raltegravir is acceptable). Two or more HIV-1 RNA determinations >200 copies/mL within 48 weeks prior to study entry. Any febrile illness (>101°F) within 30 days prior to study entry. Use of drugs with anti-CMV activity within 90 days prior to study entry, with the exception of standard dose valacyclovir and acyclovir. See the protocol for more information. Immunosuppressive or immunomodulatory drug use, with the exception of topical, inhaled, and intranasal corticosteroids within 90 days prior to study entry. See the protocol for more information. Concomitant use of prohibited medications. See the protocol for more information. Persons who are breastfeeding, pregnant or planning to become pregnant during the study. Participating in a study where co-enrollment is not allowed. Receipt of any vaccination within 14 days prior to study entry. Presence on screening ECG or a known history of atrial tachycardia (other than sinus tachycardia). Ventricular tachycardia is also an exclusion criterion. History of cardiomyopathy or congenital heart disease or evidence of advanced conduction system disease including second degree heart block Mobitz type II, third degree heart block, AV dissociation or ECG findings that may be suggestive of predisposition to arrhythmia (i.e. delta wave). Known allergy/sensitivity or any hypersensitivity to components of the study drug or its formulation. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Acute or serious illness requiring systemic treatment and/or hospitalization within 90 days prior to study entry. Known chronic active hepatitis B virus infection within the last 24 weeks prior to study entry. NOTE: Active is defined as hepatitis B surface antigen (HBsAg) positive and hepatitis B DNA (HBV DNA) positive. Persons with HBV DNA below level of quantification (BLQ) for >24 weeks prior to study entry are eligible. 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) RNA level. Persons with HCV RNA BLQ for >24 weeks prior to study entry are eligible. Presence of history of conditions that could account for impaired neuropsychological performance (if present), including head injury with prolonged (>1 hour) loss of consciousness, central nervous system infection (e.g. encephalitis), severe learning disability, psychosis, and/or active drug or alcohol use, or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. History of multi-class HIV drug resistance or intolerance, such that in the opinion of the investigator, an alternative fully active antiretroviral regimen cannot be constructed should the participant experience loss of viral suppression on their current regimen during the study.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Letermovir<br>Letermovir 480 mg will be administered by one of the following strategies: Letermovir 240 mg tablets administered orally as two tablets once daily with or without food. Letermovir 480 mg tablets administered orally as one tablet once daily with or without food. Participants will be able to switch administration strategy during treatment duration based on availability of study supply. | Drug: Letermovir 240 MG Oral Tablet<br>* 240 mg tablets. Administered orally as two tablets once daily with or without food.<br>* Other names: PREVYMIS;Drug: Letermovir 480 MG Oral Tablet<br>* 480 mg tablet. Administered orally as one tablet once daily with or without food.<br>* Other names: PREVYMIS;Drug: Combination ART<br>* ART (antiretroviral therapy) medications will be prescribed by participants' health care providers. ARV medications will not be provided by the study.<br>|
| Other: Arm B: No anti-CMV treatment<br> | Drug: Combination ART<br>* ART (antiretroviral therapy) medications will be prescribed by participants' health care providers. ARV medications will not be provided by the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from the average at baseline (entry and treatment initiation visits) in sTNFRII at week 48 | sTNFRII (plasma soluble receptor for tumor necrosis factor type II) analyzed using ELISA. | Baseline and weeks 46 and 48. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Grade ≥3 AEs | Incidence of Grade ≥3 adverse events (AEs) after initiation of study treatment. AEs defined in version 2.0 of the DAIDS EAE Manual. | Baseline and week 60 | 
| Mucosal CMV DNA levels | Mucosal samples are from throat wash, seminal plasma and cervicovaginal swabs, Measured by PCR (polymerase chain reaction) analysis. | Measured through week 60 | 
| Plasma CMV DNA levels | Measured by PCR (polymerase chain reaction) analysis. | Measured through week 60 | 
| Change from baseline in sCD163 at week 8 | Measured by serum analysis using ELISA. | Baseline and week 8 | 
| Change from baseline in sCD163 at week 46 | Measured by serum analysis using ELISA. | Baseline and week 46 | 
| Change from baseline in sCD163 at week 48 | Measured by serum analysis using ELISA. | Baseline and week 48 | 
| Change from baseline in sCD163 at week 52 | Measured by serum analysis using ELISA. | Baseline and week 52 | 
| Change from baseline in sCD163 at week 60 | Measured by serum analysis using ELISA | Baseline and week 60 | 
| Change from baseline in sTNFRII at week 8 | Measured using ELISA. | Baseline and week 8 | 
| Change from baseline in sTNFRII at week 52 | Measured using ELISA. | Baseline and week 52 | 
| Change from baseline in sTNFRII at week 60 | Measured using ELISA. | Baseline and week 60 |