HIV
Conditions
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.
Interventions
DRUGLetermovir
Letermovir 480mg PO once daily
Sponsors
Royal Free Hospital NHS Foundation Trust
University College, London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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 Main
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in activation in global CD8 T cells in response to letermovir. | Baseline, weeks 4, 8, 12, 16 and 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quantitative analysis of T cell subsets/detailed phenotypic profile will be performed as part of the exploratory analysis | Baseline, weeks 12 and 24 | Quantitative analysis of T cell subsets/detailed phenotypic profile will be performed as part of the exploratory analysis |
| Characterization of NK profile and function in response to Letermovir | Baseline, weeks 4, 8, 12, 16 and 24 | To assess the effect of CMV replication inhibition with letermovir on NK cell phenotype and cytokine production (IFN-g/TNF) via flow cytometry. Measurement: Measured by flow cytometric analysis. |
| High resolution characterization of cells that fall between the innate and adaptive responses | Baseline, weeks 12 and 24 | To assess the effect of CMV replication inhibition with letermovir on NK-like cells (CD56+CD3+) at specified time points. Measurement: Measured by flow cytometric analysis. |
| Assessment of integrity of the intestinal barrier and how impacted by intervention | Baseline, weeks 12 and 24 | To assess the influence of CMV replication inhibition with letermovir on intestinal barrier integrity in gut biopsies. Measurement: Measured by immunohistochemistry of biopsy samples for zonula occludens-1 (ZO-1). |
| Assessment of markers of systemic inflammation and how impacted by intervention | Baseline, weeks 4, 8, 12, 16 and 24 | To assess the influence of CMV replication inhibition with letermovir on inflammatory cytokines/chemokines (IL-1, IL-6, IP10, TNF-a), sTNFRII, microbial products/activation (LPS, sCD14, CRP), intestinal damage marker (iFABP), vascular dysfunction markers (sICAM-1, sVCAM-1) in the blood of people with HIV. Measurement: Measured by ELISA. |
| 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 | To assess CMV DNA and HIV RNA in gut biopsies and the effect of intervention. Measurement: Measured by quantitative PCR analysis and in situ hybridisation. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Higher resolution analysis of specific responses to peptide level and how impacted by intervention | Baseline, weeks 4, 8, 12, 16 and 24 | To assess the influence of letermovir on CMV and HIV-specific T cell responses to peptide stimulation via multiparameter intracellular cytokine staining. Expression of cytokines, such as IFN-γ, TNF and IL-2, and activation markers will be measured via flow cytometry in conjunction with established phenotypic and memory markers. Measurement: Measured by flow cytometric analysis |
| Standard molecular analyses of proviral and HIV transcript quantitation, both surrogate markers of persistent infection | Baseline, weeks 4, 8, 12, 16 and 24 | To assess the influence of CMV replication inhibition with letermovir on HIV DNA and Cell-associated RNA Measure: Measured by quantitative real-time PCR and droplet digital PCR (ddPCR). |
Contacts
Primary ContactKatie Spears
Backup ContactDimitra Peppa
Outcome results
None listed