CMV, Cytomegalovirus, HIV Infections
Conditions
Brief summary
This was 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 were on antiretroviral therapy (ART)-mediated suppression. Participants were randomly assigned to receive either letermovir once daily or no anti-CMV treatment, for 48 weeks. The primary hypothesis of this study was that letermovir would cause a greater reduction in plasma soluble receptor for tumor necrosis factor type II (sTNFRII) levels than no anti-CMV treatment at weeks 46/48.
Detailed description
This was 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 were randomized 1:1 to receive either letermovir or no anti-CMV treatment. The target enrollment was 180 participants. A futility analysis was planned to be performed after the first 40 participants to initiate study treatment reached their 8-week study visit. Study enrollment was to be paused after the 40th participant started the study until the results of the futility analysis were considered. This study was terminated due to futility.
Interventions
DRUGLetermovir Oral Tablet
480 mg administered orally once daily with or without food
Sponsors
Merck Sharp & Dohme LLC
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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. 2. 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. 3. 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. 4. 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. 5. CD4⁺/CD8⁺ cell count obtained within 90 days prior to study entry at any US laboratory that has a CLIA certification or its equivalent. 6. 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. 7. 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. 8. 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. 9. 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. 10. Ability and willingness of individual or legal guardian/representative to provide informed consent.
Exclusion criteria
1. 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. 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 of raltegravir is acceptable). 3. Two or more HIV-1 RNA determinations \>200 copies/mL within 48 weeks prior to study entry. 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 the exception of standard dose valacyclovir and acyclovir. See the protocol for more information. 6. 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. 7. Concomitant use of prohibited medications. See the protocol for more information. 8. Persons who are breastfeeding, pregnant or planning to become pregnant during the study. 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 sinus tachycardia). Ventricular tachycardia is also an exclusion criterion. 12. 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). 13. Known allergy/sensitivity or any hypersensitivity to components of the study drug or its formulation. 14. Active drug or alcohol use or dependence that, in the opinion of the site investigator, 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 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. 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) RNA level. Persons with HCV RNA BLQ for \>24 weeks prior to study entry are eligible. 18. 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. 19. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change (Absolute) in sTNFRII | Measured at Baseline and Weeks 46 and 48 | The absolute change in sTNFRII from Baseline (average of study entry and treatment initiation visits) to Week 46/48 (average of Week 46 and Week 48), or the latest result in the treatment phase. Linear regression was used to estimate the mean change. The covariates were study arm and the gender and CD4 stratification factors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change in Odds of Oral CMV DNA Detection | Measured at Baseline and Weeks 8, 46, 48, 52 and 60 | When the number of detection outcomes was sufficient, binary repeated oral CMV DNA detection (yes/no) was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm. Due to the small sample size and small number of detectable CMV DNA results, the GEE model was not able to provide estimates. Cross-sectional CMV DNA detection summaries have been provided instead. |
| Rate of Change in Odds of Genital CMV DNA Detection | Measured at Baseline and Weeks 8, 46, 48, 52 and 60 | When the number of detection outcomes was sufficient, binary repeated genital CMV DNA detection (yes/no) was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm. The model estimates do not reflect the odds of detection, but rather, the change in the odds of detection per week on the multiplicative scale. |
| Rate of Change in Odds of Rectal CMV DNA Detection | Measured at Baseline and Weeks 8, 48 and 60 | When the number of detection outcomes was sufficient, binary repeated rectal CMV DNA detection (yes/no) was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm. Due to the small sample size and small number of detectable CMV DNA results, the GEE model was not able to provide estimates. Cross-sectional CMV DNA detection summaries have been provided instead. |
| Occurrence of Grade ≥3 AEs or Confirmed HIV-1 Virologic Failure | Measured from study entry through Week 48 | Adverse events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017. Adverse events were graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Confirmed virologic failure was defined as two consecutive HIV-1 RNA levels ≥200 copies/mL by real-time HIV-1 RNA testing. Participants with a plasma HIV-1 RNA ≥200 copies/mL at any visit had a confirmatory viral load obtained as soon as possible but within 14 days after the first sample was drawn, if possible. If the consecutive measurement of HIV-1 RNA was also ≥200 copies/mL, the participant was considered to have confirmed virologic failure. |
| Rate of Change in sCD163 | Measured at Baseline and Weeks 8, 24, 46, 48, 52 and 60 | Repeated, continuous sCD163 was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm. |
| Rate of Change in sTNFRII | Measured at Baseline and Weeks 8, 24, 46, 48, 52 and 60 | Repeated, continuous sTNFRII was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm. |
| Rate of Change in Odds of Plasma CMV DNA Detection | Measured at Baseline and Weeks 8, 46, 48, 52 and 60 | When the number of detection outcomes was sufficient, binary repeated plasma CMV DNA detection (yes/no) was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm. Due to the small sample size and small number of detectable CMV DNA results, the GEE model was not able to provide estimates. Cross-sectional CMV DNA detection summaries have been provided instead. |
Countries
United States
Participant flow
Recruitment details
Participants enrolled from 15 US-based sites during the recruitment period of April 2022 to December 2022.
Participants by arm
| Arm | Count |
|---|---|
| Letermovir Participants randomized to letermovir for 48 weeks followed by 12 weeks off letermovir
Letermovir Oral Tablet: 480 mg administered orally once daily with or without food | 19 |
| No Anti-CMV Treatment Participants randomized to no study intervention for 60 weeks | 22 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Found to Not Meet Eligibility Criteria After Randomization (Never Started Treatment) | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Study Terminated by Sponsor | 8 | 9 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Letermovir | No Anti-CMV Treatment | Total |
|---|---|---|---|
| Age, Continuous | 58 years | 58 years | 58 years |
| Age, Customized 40-49 years | 1 Participants | 5 Participants | 6 Participants |
| Age, Customized 50-59 years | 12 Participants | 9 Participants | 21 Participants |
| Age, Customized 60-69 years | 5 Participants | 8 Participants | 13 Participants |
| Age, Customized 70 years and above | 1 Participants | 0 Participants | 1 Participants |
| Antiretroviral Therapy Regimen BIC/FTC/TAF | 4 Participants | 7 Participants | 11 Participants |
| Antiretroviral Therapy Regimen DOR/DTG/FTC/TDF | 0 Participants | 1 Participants | 1 Participants |
| Antiretroviral Therapy Regimen DTG/3TC | 1 Participants | 2 Participants | 3 Participants |
| Antiretroviral Therapy Regimen DTG/ABC/3TC | 3 Participants | 2 Participants | 5 Participants |
| Antiretroviral Therapy Regimen DTG/FTC/TAF | 4 Participants | 2 Participants | 6 Participants |
| Antiretroviral Therapy Regimen EVG/COBI/FTC/TAF | 4 Participants | 2 Participants | 6 Participants |
| Antiretroviral Therapy Regimen RPV/CAB | 1 Participants | 2 Participants | 3 Participants |
| Antiretroviral Therapy Regimen RPV/DRV/COBI/FTC/TAF | 1 Participants | 0 Participants | 1 Participants |
| Antiretroviral Therapy Regimen RPV/DTG | 1 Participants | 2 Participants | 3 Participants |
| Antiretroviral Therapy Regimen RPV/DTG/FTC/TAF | 0 Participants | 1 Participants | 1 Participants |
| Antiretroviral Therapy Regimen RPV/FTC/TAF | 0 Participants | 1 Participants | 1 Participants |
| Body Mass Index | 27.1 kg/m^2 | 29.4 kg/m^2 | 29.4 kg/m^2 |
| Body Mass Index Category Normal (18.5-24.9) | 4 Participants | 5 Participants | 9 Participants |
| Body Mass Index Category Obese (≥30) | 9 Participants | 10 Participants | 19 Participants |
| Body Mass Index Category Overweight (25-29.9) | 5 Participants | 7 Participants | 12 Participants |
| Body Mass Index Category Underweight (<18.5) | 1 Participants | 0 Participants | 1 Participants |
| CD4 Count | 380 cells/mm^3 | 461 cells/mm^3 | 384 cells/mm^3 |
| Creatinine Clearance | 87.4 mL/min | 86.8 mL/min | 87.4 mL/min |
| eGFR | 80.0 mL/min/1.73 m^2 | 75.0 mL/min/1.73 m^2 | 77.5 mL/min/1.73 m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 22 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hemoglobin | 14.2 g/dL | 14.2 g/dL | 14.2 g/dL |
| HIV-1 RNA <128 copies/mL | 1 Participants | 0 Participants | 1 Participants |
| HIV-1 RNA <20 copies/mL | 11 Participants | 13 Participants | 24 Participants |
| HIV-1 RNA <40 copies/mL | 5 Participants | 6 Participants | 11 Participants |
| HIV-1 RNA ≥Lower Limit of Quantification | 2 Participants | 3 Participants | 5 Participants |
| HIV-1 RNA | 1.49 log10 copies/mL | 1.49 log10 copies/mL | 1.49 log10 copies/mL |
| Platelet Count | 215000 platelets/mm^3 | 231500 platelets/mm^3 | 215000 platelets/mm^3 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 8 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 13 Participants | 22 Participants |
| Screening CD4+ T-cell Count <350 cells/mm^3 | 9 Participants | 9 Participants | 18 Participants |
| Screening CD4+ T-cell Count ≥350 cells/mm^3 | 10 Participants | 13 Participants | 23 Participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 14 Participants | 15 Participants | 29 Participants |
| Sex/Gender, Customized Sex at Birth and Use of Gender-Affirming Hormones Female not taking testosterone (or do not know) | 5 Participants | 7 Participants | 12 Participants |
| Sex/Gender, Customized Sex at Birth and Use of Gender-Affirming Hormones Male not taking feminizing hormones (or do not know) | 14 Participants | 15 Participants | 29 Participants |
| Soluble TNF Receptor Type II | 3.37 log10 pg/mL | 3.39 log10 pg/mL | 3.39 log10 pg/mL |
| Soluble TNF Receptor Type II (sTNFRII) | 3.39 log10 pg/mL STANDARD_DEVIATION 0.12 | 3.40 log10 pg/mL STANDARD_DEVIATION 0.1 | 3.39 log10 pg/mL STANDARD_DEVIATION 0.11 |
| Weight | 90.9 kg | 87.9 kg | 90.3 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 22 |
| other Total, other adverse events | 9 / 19 | 5 / 22 |
| serious Total, serious adverse events | 1 / 19 | 1 / 22 |
Outcome results
Primary
Change (Absolute) in sTNFRII
The absolute change in sTNFRII from Baseline (average of study entry and treatment initiation visits) to Week 46/48 (average of Week 46 and Week 48), or the latest result in the treatment phase. Linear regression was used to estimate the mean change. The covariates were study arm and the gender and CD4 stratification factors.
Time frame: Measured at Baseline and Weeks 46 and 48
Population: Per-protocol population: All mITT participants who did not prematurely discontinue study product prior to Week 8, had self-reported adherence \>50% (letermovir arm only) and did not have a confirmed HIV-1 virologic failure during the treatment phase.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Letermovir | Change (Absolute) in sTNFRII | -0.028 log10 pg/mL |
| No Anti-CMV Treatment | Change (Absolute) in sTNFRII | 0.003 log10 pg/mL |
p-value: 0.295% CI: [-0.08, 0.018]Regression, Linear
Secondary
Occurrence of Grade ≥3 AEs or Confirmed HIV-1 Virologic Failure
Adverse events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017. Adverse events were graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Confirmed virologic failure was defined as two consecutive HIV-1 RNA levels ≥200 copies/mL by real-time HIV-1 RNA testing. Participants with a plasma HIV-1 RNA ≥200 copies/mL at any visit had a confirmatory viral load obtained as soon as possible but within 14 days after the first sample was drawn, if possible. If the consecutive measurement of HIV-1 RNA was also ≥200 copies/mL, the participant was considered to have confirmed virologic failure.
Time frame: Measured from study entry through Week 48
Population: Modified intent to treat population: all eligible, randomized participants excluding letermovir arm participants who did not initiate study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Letermovir | Occurrence of Grade ≥3 AEs or Confirmed HIV-1 Virologic Failure | 5 Participants |
| No Anti-CMV Treatment | Occurrence of Grade ≥3 AEs or Confirmed HIV-1 Virologic Failure | 2 Participants |
p-value: 0.1995% CI: [-0.073, 0.438]Chan/Zhang exact test diff. proportions
Secondary
Rate of Change in Odds of Genital CMV DNA Detection
When the number of detection outcomes was sufficient, binary repeated genital CMV DNA detection (yes/no) was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm. The model estimates do not reflect the odds of detection, but rather, the change in the odds of detection per week on the multiplicative scale.
Time frame: Measured at Baseline and Weeks 8, 46, 48, 52 and 60
Population: Per-protocol population: All mITT participants who did not prematurely discontinue study product prior to Week 8, had self-reported adherence \>50% (letermovir arm only) and did not have a confirmed HIV-1 virologic failure during the treatment phase.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Letermovir | Rate of Change in Odds of Genital CMV DNA Detection | Early treatment phase | 0.94 change in odds of detection per week |
| Letermovir | Rate of Change in Odds of Genital CMV DNA Detection | Late treatment phase | 0.95 change in odds of detection per week |
| Letermovir | Rate of Change in Odds of Genital CMV DNA Detection | Post treatment phase | 1.05 change in odds of detection per week |
| No Anti-CMV Treatment | Rate of Change in Odds of Genital CMV DNA Detection | Early treatment phase | 1.04 change in odds of detection per week |
| No Anti-CMV Treatment | Rate of Change in Odds of Genital CMV DNA Detection | Late treatment phase | 1.03 change in odds of detection per week |
| No Anti-CMV Treatment | Rate of Change in Odds of Genital CMV DNA Detection | Post treatment phase | 0.89 change in odds of detection per week |
Comparison: Early treatment phase comparisonp-value: 0.1295% CI: [0.8, 1.03]GEE model for repeated binary outcomes
Comparison: Late treatment phase comparisonp-value: 0.00995% CI: [0.87, 0.98]GEE model for repeated binary outcomes
Comparison: Post treatment phase comparisonp-value: 0.2495% CI: [0.9, 1.53]GEE model for repeated binary outcomes
Secondary
Rate of Change in Odds of Oral CMV DNA Detection
When the number of detection outcomes was sufficient, binary repeated oral CMV DNA detection (yes/no) was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm. Due to the small sample size and small number of detectable CMV DNA results, the GEE model was not able to provide estimates. Cross-sectional CMV DNA detection summaries have been provided instead.
Time frame: Measured at Baseline and Weeks 8, 46, 48, 52 and 60
Population: Per-protocol population: All mITT participants who did not prematurely discontinue study product prior to Week 8, had self-reported adherence \>50% (letermovir arm only) and did not have a confirmed HIV-1 virologic failure during the treatment phase.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Baseline | Detected | 2 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Baseline | Not detected | 15 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Baseline | No result | 0 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 8 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 8 | Not detected | 15 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 8 | No result | 2 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 46 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 46 | Not detected | 12 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 46 | No result | 5 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 48 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 48 | Not detected | 13 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 48 | No result | 4 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 52 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 52 | Not detected | 12 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 52 | No result | 5 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 60 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 60 | Not detected | 8 Participants |
| Letermovir | Rate of Change in Odds of Oral CMV DNA Detection | Week 60 | No result | 9 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 52 | Not detected | 11 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Baseline | Detected | 1 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 48 | Detected | 1 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Baseline | Not detected | 20 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 60 | No result | 14 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Baseline | No result | 1 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 48 | Not detected | 17 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 8 | Detected | 1 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 52 | No result | 10 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 8 | Not detected | 19 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 48 | No result | 4 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 8 | No result | 2 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 60 | Not detected | 6 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 46 | Detected | 1 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 52 | Detected | 1 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 46 | Not detected | 15 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 60 | Detected | 2 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Oral CMV DNA Detection | Week 46 | No result | 6 Participants |
Secondary
Rate of Change in Odds of Plasma CMV DNA Detection
When the number of detection outcomes was sufficient, binary repeated plasma CMV DNA detection (yes/no) was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm. Due to the small sample size and small number of detectable CMV DNA results, the GEE model was not able to provide estimates. Cross-sectional CMV DNA detection summaries have been provided instead.
Time frame: Measured at Baseline and Weeks 8, 46, 48, 52 and 60
Population: Per-protocol population: All mITT participants who did not prematurely discontinue study product prior to Week 8, had self-reported adherence \>50% (letermovir arm only) and did not have a confirmed HIV-1 virologic failure during the treatment phase.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Baseline | No result | 0 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Baseline | No detected | 17 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Baseline | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 8 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 8 | No detected | 16 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 8 | No result | 1 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 46 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 46 | No detected | 13 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 46 | No result | 4 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 48 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 48 | No detected | 13 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 48 | No result | 4 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 52 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 52 | No detected | 11 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 52 | No result | 6 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 60 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 60 | No detected | 7 Participants |
| Letermovir | Rate of Change in Odds of Plasma CMV DNA Detection | Week 60 | No result | 10 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 52 | No detected | 11 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Baseline | No result | 2 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Baseline | Detected | 0 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 48 | Detected | 0 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Baseline | No detected | 20 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 60 | No result | 14 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 48 | No detected | 18 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 8 | Detected | 0 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 52 | No result | 11 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 8 | No detected | 20 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 48 | No result | 4 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 8 | No result | 2 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 60 | No detected | 8 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 46 | Detected | 0 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 52 | Detected | 0 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 46 | No detected | 16 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 60 | Detected | 0 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Plasma CMV DNA Detection | Week 46 | No result | 6 Participants |
Secondary
Rate of Change in Odds of Rectal CMV DNA Detection
When the number of detection outcomes was sufficient, binary repeated rectal CMV DNA detection (yes/no) was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm. Due to the small sample size and small number of detectable CMV DNA results, the GEE model was not able to provide estimates. Cross-sectional CMV DNA detection summaries have been provided instead.
Time frame: Measured at Baseline and Weeks 8, 48 and 60
Population: Per-protocol population: All mITT participants who did not prematurely discontinue study product prior to Week 8, had self-reported adherence \>50% (letermovir arm only) and did not have a confirmed HIV-1 virologic failure during the treatment phase.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Baseline | Detected | 1 Participants |
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Baseline | Not detected | 16 Participants |
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Baseline | No result | 0 Participants |
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Week 8 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Week 8 | Not detected | 15 Participants |
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Week 8 | No result | 2 Participants |
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Week 48 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Week 48 | Not detected | 14 Participants |
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Week 48 | No result | 3 Participants |
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Week 60 | Detected | 0 Participants |
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Week 60 | Not detected | 7 Participants |
| Letermovir | Rate of Change in Odds of Rectal CMV DNA Detection | Week 60 | No result | 10 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Week 60 | Not detected | 8 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Baseline | Detected | 1 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Week 48 | Detected | 2 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Baseline | Not detected | 21 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Week 60 | Detected | 0 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Baseline | No result | 0 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Week 48 | Not detected | 15 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Week 8 | Detected | 0 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Week 60 | No result | 14 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Week 8 | Not detected | 20 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Week 48 | No result | 5 Participants |
| No Anti-CMV Treatment | Rate of Change in Odds of Rectal CMV DNA Detection | Week 8 | No result | 2 Participants |
Secondary
Rate of Change in sCD163
Repeated, continuous sCD163 was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm.
Time frame: Measured at Baseline and Weeks 8, 24, 46, 48, 52 and 60
Population: Per-protocol population: All mITT participants who did not prematurely discontinue study product prior to Week 8, had self-reported adherence \>50% (letermovir arm only) and did not have a confirmed HIV-1 virologic failure during the treatment phase.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Letermovir | Rate of Change in sCD163 | Early treatment phase | 0.0012 log10 ng/mL/week |
| Letermovir | Rate of Change in sCD163 | Late treatment phase | -0.0005 log10 ng/mL/week |
| Letermovir | Rate of Change in sCD163 | Post treatment phase | 0.0028 log10 ng/mL/week |
| No Anti-CMV Treatment | Rate of Change in sCD163 | Early treatment phase | 0.0010 log10 ng/mL/week |
| No Anti-CMV Treatment | Rate of Change in sCD163 | Late treatment phase | 0.0002 log10 ng/mL/week |
| No Anti-CMV Treatment | Rate of Change in sCD163 | Post treatment phase | -0.0028 log10 ng/mL/week |
Comparison: Early treatment phase comparisonp-value: 0.9595% CI: [-0.0062, 0.0066]GEE model for repeated outcomes
Comparison: Late treatment phase comparisonp-value: 0.2895% CI: [-0.0019, 0.0005]GEE model for repeated outcomes
Comparison: Post treatment phase comparisonp-value: 0.07795% CI: [-0.0006, 0.0118]GEE model for repeated outcomes
Secondary
Rate of Change in sTNFRII
Repeated, continuous sTNFRII was modeled with generalized estimating equations (GEE) to estimate the weekly rate of change (slope). The covariates were study arm and the gender and CD4 stratification factors, as well as a three-level period effect (early treatment phase \[through Week 8\], late treatment phase, post-treatment phase) and its interaction with the study arm.
Time frame: Measured at Baseline and Weeks 8, 24, 46, 48, 52 and 60
Population: Per-protocol population: All mITT participants who did not prematurely discontinue study product prior to Week 8, had self-reported adherence \>50% (letermovir arm only) and did not have a confirmed HIV-1 virologic failure during the treatment phase.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Letermovir | Rate of Change in sTNFRII | Early treatment phase | 0.0009 log10 pg/mL/week |
| Letermovir | Rate of Change in sTNFRII | Late treatment phase | -0.0010 log10 pg/mL/week |
| Letermovir | Rate of Change in sTNFRII | Post treatment phase | 0.0001 log10 pg/mL/week |
| No Anti-CMV Treatment | Rate of Change in sTNFRII | Early treatment phase | 0.0000 log10 pg/mL/week |
| No Anti-CMV Treatment | Rate of Change in sTNFRII | Late treatment phase | -0.0001 log10 pg/mL/week |
| No Anti-CMV Treatment | Rate of Change in sTNFRII | Post treatment phase | -0.0021 log10 pg/mL/week |
Comparison: Early treatment phase comparisonp-value: 0.7295% CI: [-0.004, 0.0058]GEE model for repeated outcomes
Comparison: Late treatment phase comparisonp-value: 0.1395% CI: [-0.0022, 0.0003]GEE model for repeated outcomes
Comparison: Post treatment phase comparisonp-value: 0.1795% CI: [-0.001, 0.0055]GEE model for repeated outcomes