Clinical Trial to Evaluate the Effects of Letermovir Prophylaxis on T-cell Immune Activation in Participants With Treated HIV-1 Infection

NCT06626555 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: 1250962020-000288-22
• Study Type: interventional
• Target: 36
• Locations: 0 countries
• Sites: N/A

Brief Summary

People living with HIV (PLWH), even with an undetectable viral load (VL) on antiretroviral treatment (ART), develop health conditions, such as heart disease, diabetes, various cancers, and conditions that can affect the brain, more commonly than the general population. These conditions occur earlier in PLWH compared to HIV negative individuals with similar lifestyles. Ongoing inflammation in the body despite antiretroviral therapy is thought to be contributing to the development of these conditions that can affect healthy ageing in PLWH. Cytomegalovirus (CMV) is a very common infection in PLWH and is an important driver of inflammation in the body that can affect the function of the immune immune cells in the body (defense system) causing unwanted activation and damage of the gut making it more leaky. A drug with potent activity against CMV called valganciclovir has previously shown to reduce this potentially damaging inflammation in the body. In this study, the investigators want to investigate if a new drug called Letermovir, in combination with HIV treatment, will prevent CMV from replicating (multiplying), and thereby reduce inflammation in the body. Letermovir has received approval to prevent CMV from multiplying in patients receiving bone marrow transplants. It has been shown to have a more favourable side-effect profile compared to other available drugs and is predicted to interact little with anti-HIV drugs. The aim of this study is to find out if the letermovir is safe and effective in reducing CMV related immune activation and inflammation PLWH. These findings will be used to help us design larger studies to identify individuals who would benefit most from this treatment to prevent the development of health conditions that can affect their quality of life.

Conditions

HIV

Outcome Measures

Primary Outcomes (1)

• Change in activation in global CD8 T cells in response to letermovir.

  To assess the effect of CMV replication inhibition with letermovir on activated (HLADR+CD38+) CD8 T cell percentage using flow cytometry analysis at specified time frames. Measurement: Measured by flow cytometric analysis.

  Baseline, weeks 4, 8, 12, 16 and 24

Secondary Outcomes (6)

• Quantitative analysis of T cell subsets/detailed phenotypic profile will be performed as part of the exploratory analysis

  Baseline, weeks 12 and 24

• Characterization of NK profile and function in response to Letermovir

  Baseline, weeks 4, 8, 12, 16 and 24

• High resolution characterization of cells that fall between the innate and adaptive responses

  Baseline, weeks 12 and 24

• Determine the extent of CMV and HIV replication in the gut of HIV-positive individuals and how impacted by intervention

  Baseline, weeks 12 and 24

• Assessment of integrity of the intestinal barrier and how impacted by intervention

  Baseline, weeks 12 and 24

Other Outcomes (2)

• Higher resolution analysis of specific responses to peptide level and how impacted by intervention

  Baseline, weeks 4, 8, 12, 16 and 24

• Standard molecular analyses of proviral and HIV transcript quantitation, both surrogate markers of persistent infection

  Baseline, weeks 4, 8, 12, 16 and 24

Study Arms (2)

Letermovir

EXPERIMENTAL

Letermovir 480mg PO once daily

Drug: Letermovir

Standard of Care

NO INTERVENTION

Standard of care - No intervention

Interventions

Letermovir DRUG

Letermovir 480mg PO once daily

Letermovir

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Is HIV-1 antibody positive with a plasma HIV-1 RNA ≤50 copies/mL for greater than 12 months
• ≥50 years of age of any gender
• Females of childbearing potential who agree to avoid pregnancy for the duration of the trial and follow methods of contraception as detailed in section 7.1
• Has a nadir CD4 of ≤200 cells/mm3 prior to screening
• Has been on antiretroviral therapy for ≥ 6 months
• Has documented CMV IgG seropositivity within one year of trial screening
• Has an undetectable (≤168 international units/mL) CMV Deoxyribonucleic acid (DNA) within 14 days prior to randomisation
• Laboratory parameters are not clinically significant as determined by the investigator
• The participant (or legally acceptable representative, if applicable) has provided written informed consent for the trial and Future Biomedical Research

You may not qualify if:

• Is HIV-1 antibody positive with a plasma HIV-1 RNA ≤50 copies/mL for greater than 12 months
• ≥50 years of age of any gender
• Females of childbearing potential who agree to avoid pregnancy for the duration of the trial and follow methods of contraception as detailed in section 7.1
• Has a nadir CD4 of ≤200 cells/mm3 prior to screening
• Has been on antiretroviral therapy for ≥ 6 months
• Has documented CMV IgG seropositivity within one year of trial screening
• Has an undetectable (≤168 international units/mL) CMV Deoxyribonucleic acid (DNA) within 14 days prior to randomisation
• Laboratory parameters are not clinically significant as determined by the investigator
• The participant (or legally acceptable representative, if applicable) has provided written informed consent for the trial and Future Biomedical Research
• Has a history of ulcerative colitis or Crohn's disease or active colitis within 6 months prior to randomisation
• Has a history of CMV end-organ disease within 6 months prior to randomisation
• Has significant hypersensitivity or other contraindication to any of the components of the trial drug as described in the SmPC
• Has a detectable HCV RNA or hepatitis B surface antigen (HBsAg) within 90 days prior to randomisation
• Has a history of malignancy ≤5 years prior to signing informed consent
• Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through 90 days after the last dose of trial therapy

Sponsors & Collaborators

• University College, London: lead
• Royal Free Hospital NHS Foundation Trust: collaborator

Related Publications (9)

• Hunt PW, Martin JN, Sinclair E, Epling L, Teague J, Jacobson MA, Tracy RP, Corey L, Deeks SG. Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis. 2011 May 15;203(10):1474-83. doi: 10.1093/infdis/jir060.

  PMID: 21502083 BACKGROUND

• Bradley T, Peppa D, Pedroza-Pacheco I, Li D, Cain DW, Henao R, Venkat V, Hora B, Chen Y, Vandergrift NA, Overman RG, Edwards RW, Woods CW, Tomaras GD, Ferrari G, Ginsburg GS, Connors M, Cohen MS, Moody MA, Borrow P, Haynes BF. RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses. Cell. 2018 Oct 4;175(2):387-399.e17. doi: 10.1016/j.cell.2018.08.064. Epub 2018 Sep 27.

  PMID: 30270043 BACKGROUND

• Thornhill JP, Pace M, Martin GE, Hoare J, Peake S, Herrera C, Phetsouphanh C, Meyerowitz J, Hopkins E, Brown H, Dunn P, Olejniczak N, Willberg C, Klenerman P, Goldin R, Fox J, Fidler S, Frater J; CHERUB investigators. CD32 expressing doublets in HIV-infected gut-associated lymphoid tissue are associated with a T follicular helper cell phenotype. Mucosal Immunol. 2019 Sep;12(5):1212-1219. doi: 10.1038/s41385-019-0180-2. Epub 2019 Jun 25.

  PMID: 31239514 BACKGROUND

• Amir el-AD, Davis KL, Tadmor MD, Simonds EF, Levine JH, Bendall SC, Shenfeld DK, Krishnaswamy S, Nolan GP, Pe'er D. viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat Biotechnol. 2013 Jun;31(6):545-52. doi: 10.1038/nbt.2594. Epub 2013 May 19.

  PMID: 23685480 BACKGROUND

• Levine JH, Simonds EF, Bendall SC, Davis KL, Amir el-AD, Tadmor MD, Litvin O, Fienberg HG, Jager A, Zunder ER, Finck R, Gedman AL, Radtke I, Downing JR, Pe'er D, Nolan GP. Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis. Cell. 2015 Jul 2;162(1):184-97. doi: 10.1016/j.cell.2015.05.047. Epub 2015 Jun 18.

  PMID: 26095251 BACKGROUND

• Peppa D, Pedroza-Pacheco I, Pellegrino P, Williams I, Maini MK, Borrow P. Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection. Front Immunol. 2018 Mar 16;9:474. doi: 10.3389/fimmu.2018.00474. eCollection 2018.

  PMID: 29616021 BACKGROUND

• Gupta RK, Abdul-Jawad S, McCoy LE, Mok HP, Peppa D, Salgado M, Martinez-Picado J, Nijhuis M, Wensing AMJ, Lee H, Grant P, Nastouli E, Lambert J, Pace M, Salasc F, Monit C, Innes AJ, Muir L, Waters L, Frater J, Lever AML, Edwards SG, Gabriel IH, Olavarria E. HIV-1 remission following CCR5Delta32/Delta32 haematopoietic stem-cell transplantation. Nature. 2019 Apr;568(7751):244-248. doi: 10.1038/s41586-019-1027-4. Epub 2019 Mar 5.

  PMID: 30836379 BACKGROUND

• Gupta RK, Peppa D, Hill AL, Galvez C, Salgado M, Pace M, McCoy LE, Griffith SA, Thornhill J, Alrubayyi A, Huyveneers LEP, Nastouli E, Grant P, Edwards SG, Innes AJ, Frater J, Nijhuis M, Wensing AMJ, Martinez-Picado J, Olavarria E. Evidence for HIV-1 cure after CCR5Delta32/Delta32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report. Lancet HIV. 2020 May;7(5):e340-e347. doi: 10.1016/S2352-3018(20)30069-2. Epub 2020 Mar 10.

  PMID: 32169158 BACKGROUND

• Alrubayyi A, Gea-Mallorqui E, Touizer E, Hameiri-Bowen D, Kopycinski J, Charlton B, Fisher-Pearson N, Muir L, Rosa A, Roustan C, Earl C, Cherepanov P, Pellegrino P, Waters L, Burns F, Kinloch S, Dong T, Dorrell L, Rowland-Jones S, McCoy LE, Peppa D. Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV. Nat Commun. 2021 Oct 5;12(1):5839. doi: 10.1038/s41467-021-26137-7.

  PMID: 34611163 BACKGROUND

MeSH Terms

Interventions

letermovir

Central Study Contacts

Katie Spears

CONTACT

+44 020 7472 6232; k.spears@nhs.net

Dimitra Peppa

CONTACT

d.peppa@ucl.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 14, 2024
• First Posted: October 4, 2024
• Study Start: October 1, 2024
• Primary Completion: March 1, 2026
• Study Completion: March 1, 2026
• Last Updated: October 4, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share