# Impact of Treating Asymptomatic CMV Replication on Cardiovascular Risk in Treated HIV Infection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $668,476

## Abstract

PROJECT SUMMARY
Despite modern antiretroviral therapy (ART), people living with HIV (PLWH) have an approximately 50%
increased risk of cardiovascular disease. While persistent systemic inflammation appears to predict this risk,
the optimal strategies to reduce inflammation and cardiovascular risk in treated HIV infection remain undefined.
The overarching hypothesis of this proposal is that asymptomatic cytomegalovirus (CMV) replication is an
important mediator of cardiovascular risk in treated HIV infection. This hypothesis is supported by the fact that
CMV replicates in vascular endothelium and appears to play a role in atherosclerosis in immunocompromised
solid-organ transplant recipients. Furthermore, over 90% of PLWH have asymptomatic CMV co-infection, CMV
shedding levels are higher in treated PLWH than in the general population, surrogate markers of CMV are
associated with vascular disease and myocardial infarction risk in treated HIV, and treating asymptomatic CMV
replication in an earlier trial reduced the inflammatory pathways (i.e., sTNFR2) that most strongly predict
vascular disease in treated HIV. Yet, no study has assessed whether treating asymptomatic CMV replication
in treated PLWH reduces vascular inflammation and markers of endothelial dysfunction. Our proposal
addresses these issues by leveraging a separately funded placebo-controlled clinical trial led by Dr. Hunt of the
novel CMV terminase inhibitor letermovir in 180 ART-suppressed PLWH in the ACTG (A5383). Aim 1 will
determine whether 48 weeks of letermovir reduces vascular inflammation as assessed by FDG-PET/CT in a
subset of 92 participants. Aim 2 will assess whether letermovir reduces plasma markers of endothelial
dysfunction and Aim 3 will characterize the plasma proteomic signatures that are altered by letermovir therapy
using a modified aptamer assay and relate these changes to concurrent changes in vascular inflammation.
These studies also benefit from a strong MPI team with complementary expertise and a long history of
collaboration including Drs. Hunt (HIV immunopathogenesis, clinical trials), Tawakol (cardiology, FDG-PET/CT
imaging), and Hsue (HIV cardiology, clinical trials); a team of co-Is with proteomics and bioinformatics
expertise (Drs. Ganz and Olshen); and the largest HIV therapeutics clinical trials network in the world (ACTG).
Collectively, these studies will test for the first time treated HIV infection – and more broadly in humans - a
potential causal role of asymptomatic CMV replication in vascular disease in the context of a rigorously
designed clinical trial. If successful, this study could help motivate a future Phase 3 trial of letermovir to reduce
cardiovascular events among other complications in treated HIV infection.

## Key facts

- **NIH application ID:** 10242227
- **Project number:** 5R01HL152957-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** PETER W HUNT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $668,476
- **Award type:** 5
- **Project period:** 2020-08-20 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242227

## Citation

> US National Institutes of Health, RePORTER application 10242227, Impact of Treating Asymptomatic CMV Replication on Cardiovascular Risk in Treated HIV Infection (5R01HL152957-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10242227. Licensed CC0.

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