Looking to letermovir to reduce inflammation and other issues in people with HIV

CATIE News

Want to receive publications straight to your inbox?

CATIE
CATIE News 06162022
  • Despite the use of HIV treatment (ART), people with HIV have subtle but persistent immunological issues
  • Some immunological issues may be caused by co-infection with the common virus cytomegalovirus (CMV)
  • McGill University scientists launched a clinical trial of the drug letermovir to try to suppress CMV

Receive CATIE News in your inbox:

HIV treatment (ART) is highly effective at suppressing levels of HIV in the blood. Over time, continued use of ART as prescribed keeps HIV suppressed and helps the immune system to effect repairs. The power of ART is so transformative that researchers project that many ART users will have near-normal life expectancy.

However, ART does not heal all immunological injury in people with HIV. Many subtle immune-related issues persist, such as the following:

  • There are excessive levels of immune activation and inflammation. Scientists say that these likely contribute to a wide range of issues that could, over the long term, affect health. These can include cardiovascular disease, kidney disease, type 2 diabetes, degenerative issues that affect the brain, excessive fat in the liver and thinning of the bones. 
  • HIV infection weakens the barrier in the gut that prevents harmful proteins produced by bacteria and fungi from getting into the body and absorbed into blood. Once inside in the blood, these proteins can incite inflammation and keep the immune system activated.
  • Some cells of the immune systems of people with HIV appear to be prematurely aged, possibly from chronic excess inflammation and immune activation.

The underlying cause of excess immune activation and inflammation in people with HIV who are taking ART is not clear and is being studied. Some scientists think that a common member of the herpes virus family called CMV likely contributes to excess inflammation and immune activation, as well as premature aging of the immune system.

CMV – then and now

Before ART became widely available in Canada and other high-income countries, CMV was associated with serious complications, most commonly blindness in people with HIV.

Today, thanks to ART, serious acute CMV-related disease is rare among people with HIV. However, scientists think that low-level CMV production in ART users may contribute to health issues related to chronic inflammation

In HIV-negative people, CMV has been linked to premature aging of the immune system and a reduced ratio of two important groups of the immune system’s cells—the CD4/CD8 ratio. Therefore, it is at least plausible that CMV has a similar impact in some people with HIV.

An early clinical trial to suppress CMV

More than a decade ago, researchers in the U.S. conducted a small placebo-controlled study with the drug valganciclovir in people with HIV who were taking ART. Valganciclovir is approved to treat CMV-related disease. The researchers found that valganciclovir (900 mg per day) was able to reduce excess immune activation. However, the trial had a short duration because valganciclovir is toxic to the bone marrow over the long term.

Suppressing CMV today with letermovir

In the past several years, a new anti-CMV drug called letermovir (Prevymis) has been approved by regulatory authorities in Canada and other countries. It is most commonly used in people who are receiving organ transplants, as this population takes certain medicines to suppress their immune systems from attacking the transplanted organ. By weakening the immune system, transplant medicines can inadvertently allow CMV to become reactivated and cause disease. Clinical trials have found that letermovir is generally safe in people who have organ transplants. Letermovir works by blocking the ability of CMV-infected cells to produce new copies of this virus.

A study in Quebec

A team of scientists at McGill University in Montreal, Quebec, led by Jean-Pierre Routy, MD, PhD, and Léna Royston, MD, PhD, is interested in trying to find ways to reduce excess inflammation and repair the integrity of the barrier in the gut in people with chronic HIV infection. The scientists have launched a clinical trial of letermovir for people with HIV who have been taking ART and whose HIV viral load is suppressed. Potential volunteers will be adults with a CD4+ count of at least 400 cells/mm3. The McGill researchers estimate that about 85% of people with HIV in Canada also have CMV infection, and potential volunteers will be screened for CMV at the study site to be sure that they have this virus.

In this clinical trial, letermovir will be taken orally at a dose of 480 mg once daily for 14 consecutive weeks. After this time, monitoring will continue for an additional 12 weeks. Letermovir is generally safe but can cause mild nausea in a minority of users.

The scientists plan to recruit 60 adults who will be assigned to the following two groups:

  • ART + letermovir – 40 people
  • ART alone – 20 people

The research team plans extensive laboratory tests to assess at least the following: changes in inflammation in blood and tissue, the passage of proteins from bacteria and fungi across the gut, and changes to T-cells in the blood. A sub-study will also take tiny samples of tissue from the colon for further analysis.

Healthcare providers who have patients eligible and interested in this research can contact the following people for further information:

The study will be taking place at the following sites:

  • Chronic Viral Illness Service, McGill University Health Centre, Montréal
  • Clinique d’infectiologie virale chronique, Centre Hospitalier de l’Université de Montréal, Montréal
  • Clinique médicale l’Actuel, Montréal
  • Centre de recherche du CHU de Québec, Quebec City

The McGill letermovir trial is an important step forward to try to reverse the ongoing immunological issues that likely contribute to a range of chronic health conditions in people with HIV.

In the U.S.

The U.S. government-funded AIDS Clinical Trials Group (ACTG) is about to start a trial of letermovir in people with HIV who are taking ART and have a suppressed viral load. The ACTG trial, code-named A5383, is different from the Canadian study, as it will be longer and will largely focus on changes in inflammation in the blood. The U.S. study will assess the effect of the drug in people who are over the age of 40 and in some people who have less than 350 CD4+ cells/mm3. In the U.S. study, half of the participants will receive ART + letermovir, while the other half will stay on ART alone.

For the future

It is good that these two different clinical trials in people with HIV are happening because there are many aspects of CMV’s impact on the immune system that have long been overdue for study. The data from the letermovir trials in Canada and the U.S. will complement each other and should reveal much about the immune system and CMV.

—Sean R. Hosein

REFERENCES:

  1. Routy JP, Royston L, Isnard S. Aging with grace for people living with HIV: Strategies to overcome leaky gut and cytomegalovirus coinfection. JAIDS. 2022 Feb 1;89(Suppl 1):S29-S33. 
  2. Schnittman SR, Hunt PW. Clinical consequences of asymptomatic cytomegalovirus in treated human immunodeficiency virus infection. Current Opinion in HIV/AIDS. 2021 May 1;16(3):168-176.
  3. Schnittman SR, Deitchman AN, Beck-Engeser G, et al. Abnormal levels of some biomarkers of immune activation despite very early treatment of human immunodeficiency virus. Journal of Infectious Diseases. 2021 May 20;223(9):1621-1630. 
  4. Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nature Medicine. 2019 Dec;25(12):1822-1832.
  5. Medzhitov R. The spectrum of inflammatory responses. Science. 2021 Nov 26;374(6571):1070-1075.
  6. Barrett L, Stapleton SN, Fudge NJ, et al. Immune resilience in HIV-infected individuals seronegative for cytomegalovirus. AIDS. 2014 Sep 10;28(14):2045-9. 
  7. Heath JJ, Fudge NJ, Gallant ME, et al. Proximity of cytomegalovirus-specific CD8+ T cells to replicative senescence in human immunodeficiency virus-infected individuals. Frontiers in Immunology. 2018 Feb 15;9:201.
  8. Royston L, Isnard S, Lin J, et al. Cytomegalovirus as an uninvited guest in the response to vaccines in people living with HIV. Viruses. 2021 Jun 29;13(7):1266.
  9. Isnard S, Ramendra R, Lin J, et al. Anti-cytomegalovirus immunoglobulin G is linked to CD4 T-cell count decay in human immunodeficiency virus (HIV) elite controllers. Clinical Infectious Diseases. 2021 Jul 1;73(1):144-147.
  10. Ramendra R, Isnard S, Lin J, et al. Cytomegalovirus seropositivity is associated with increased microbial translocation in people living with human immunodeficiency virus and uninfected controls. Clinical Infectious Diseases. 2020 Sep 12;71(6):1438-1446.
  11. Heath J, Grant M. The immune response against human cytomegalovirus links cellular to systemic senescence. Cells. 2020 Mar 20;9(3):766. 
  12. Zhang W, Li H, Bream JH, et al. Longitudinal association of cytokine-producing CMV-specific T cells with frailty in HIV-infected and -uninfected men who have sex with men. Immunity and Ageing. 2022 Mar 7;19(1):13. 
  13. Thyagarajan B, Faul J, Vivek S, et al. Age-related differences in T cell subsets in a nationally representative sample of people over age 55: Findings from the Health and Retirement Study. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2021 Oct 11:glab300. 
  14. Higdon LE, Gustafson CE, Ji X, et al. Association of premature immune aging and cytomegalovirus after solid organ transplant. Frontiers in Immunology. 2021 May 27;12:661551. 
  15. Ballegaard V, Pedersen KK, Brændstrup P, et al. Cytomegalovirus-specific CD8+ T-cell responses are associated with arterial blood pressure in people living with HIV. PLoS One. 2020 Jan 13;15(1):e0226182. 
  16. Strindhall J, Löfgren S, Främsth C, et al. CD4/CD8 ratio <1 is associated with lymphocyte subsets, CMV and gender in 71-year-old individuals: 5-year follow-up of the Swedish HEXA Immune Longitudinal Study. Experimental Gerontology. 2017 Sep; 95:82-87. 
  17. Nikolich-Žugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nature Immunology. 2018 Jan;19(1):10-19. 
  18. Hadrup SR, Strindhall J, Køllgaard T, et al. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. Journal of Immunology. 2006 Feb 15;176(4):2645-53. 
  19. Pangrazzi L, Weinberger B. T cells, aging and senescence. Experimental Gerontology. 2020 Feb 22; 134:110887.
  20. Rook AH, Masur H, Lane HC, et al. Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immune deficiency syndrome. Journal of Clinical Investigation. 1983 Jul;72(1):398-403.  
  21. Friedman AH, Orellana J, Freeman WR, et al. Cytomegalovirus retinitis: a manifestation of the acquired immune deficiency syndrome (AIDS). British Journal of Ophthalmology. 1983 Jun;67(6):372-80. doi: 10.1136/bjo.67.6.372. PMID: 6303386; PMCID: PMC1040068.
  22. Verboeket SO, Wit FW, Verheij E, et al. Human immunodeficiency virus (HIV)-negative men who have sex with men have higher CD8+ T-cell counts and lower CD4+/CD8+ T-cell ratios compared with HIV-negative heterosexual men. Journal of Infectious Diseases. 2021 Oct 13;224(7):1187-1197.  
  23. Ballegaard V, Pedersen KK, Brændstrup P, et al. Cytomegalovirus-specific CD8+ T-cell responses are associated with arterial blood pressure in people living with HIV. PLoS One. 2020 Jan 13;15(1):e0226182.  
  24. Ballegaard V, Brændstrup P, Pedersen KK, et al. Cytomegalovirus-specific T-cells are associated with immune senescence, but not with systemic inflammation, in people living with HIV. Scientific Reports. 2018 Feb 28;8(1):3778.  
  25. Abana CO, Pilkinton MA, Gaudieri S, et al. Cytomegalovirus (CMV) epitope-specific CD4+ T cells are inflated in HIV+ CMV+ subjects. Journal of Immunology. 2017 Nov 1;199(9):3187-3201.
  26. Wanjalla CN, McDonnell WJ, et al. Single-cell analysis shows that adipose tissue of persons with both HIV and diabetes is enriched for clonal, cytotoxic, and CMV-specific CD4+ T cells. Cell Reports Medicine. 2021 Feb 16;2(2):100205.
  27. Smith DM, Nakazawa M, Freeman ML, et al. Asymptomatic CMV replication during early human immunodeficiency virus (HIV) infection is associated with lower CD4/CD8 ratio during HIV treatment. Clinical Infectious Diseases. 2016 Dec 1;63(11):1517-1524.  
  28. Levi LI, Sharma S, Schleiss MR, et al. Cytomegalovirus viremia and risk of disease progression and death in HIV-positive patients starting antiretroviral therapy. AIDS. 2022; in press.
  29. Merck Canada. Prevymis-letermovir tablets. Product monograph. 8 May 2020.
  30. Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. New England Journal of Medicine. 2017 Dec 21;377(25):2433-2444.  
  31. Jorgenson MR, Kleiboeker H, Garg N, et al. Letermovir conversion after valganciclovir treatment in cytomegalovirus high-risk abdominal solid organ transplant recipients may promote development of cytomegalovirus-specific cell mediated immunity. Transplant Infectious Diseases. 2022 Feb;24(1): e13766.
  32.  Piret J, Goyette N, Boivin G. In vitro activity of letermovir against human cytomegalovirus isolates with different drug susceptibility phenotypes. Antiviral Research. 2022; in press.
  33. AIDS Clinical Trials Group. ACTG Launches A5383, Clinical Trial Evaluating Potential Immunologic Benefits of Treating Asymptomatic CMV in People Living with HIV. Press release. 22 April 2022.