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.

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 Exclusion criteria:

• 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
• Has received within 7 days prior to screening any of the following: ganciclovir; valganciclovir; foscarnet; acyclovir (≥ 3200 mg PO per day or ≥25 mg/kg IV per day); valaciclovir (≥3000 mg PO per day) or famciclovir (≥1500 mg PO per day).
• Has used systemic immunosuppressive therapy or immune modulators within 30 days prior to treatment in this trial or is anticipated to need them during the trial