Antiviral Drugs For Cytomegalovirus

  • Lenee Castelyn Postgraduate diploma, Public Health, University of Pretoria, South Africa

Introduction

Cytomegalovirus (CMV) is a common viral infection that can affect people of all ages, often presenting with flu-like symptoms during the first infection. While many may not realise they are infected, CMV can have severe consequences. In cases of congenital CMV, babies who are born with the virus can develop hearing loss and developmental delays. Understanding the transmission of CMV is crucial, as the virus can be spread through bodily fluids and poses risks during organ transplantation and childbirth. In the context of healthcare, antiviral drugs play a pivotal role in preventing and treating CMV infections. This article explores the use of antiviral drugs, including ganciclovir, valganciclovir, foscarnet and cidofovir in managing CMV. We also address challenges and consider new drugs on the horizon. 

Understanding Cytomegalovirus

Cytomegalovirus (CMV) is a condition that is common in people of all ages. The virus can cycle through active episodes and also dormant periods. Typically, CMW infection goes unnoticed as it doesn’t usually present with any symptoms. Having said this, some people do experience flu-like symptoms with their first infection.1 This includes:

  • High temperature 
  • Tiredness 
  • Body ache 
  • Rash on skin 
  • Nausea 
  • Swollen glands 
  • Sore throat 

Congenital CMV

Congenital CMV occurs when babies are born with the virus. The majority of infants born with CMV appear healthy at birth. However, a subgroup may develop symptoms over time. The most prevalent delayed symptoms include hearing loss and developmental delays, with a smaller percentage experiencing vision problems.2

Some infants may exhibit symptoms at birth, a few of the signs include: 

  • Premature birth 
  • Low birth weight 
  • Jaundice
  • Enlarged and poorly functioning liver 
  • Purple skin splotches, a rash, or a combination of both 
  • Microcephaly (small head)
  • Enlarged spleen
  • Pneumonia
  • Seizures 

Transmission of CMV

An active virus can be transmitted to others through bodily fluids such as blood, urine, saliva, breast milk, tears, semen and vaginal fluid. 

CMV is diagnosed with laboratory testing of blood, bodily fluids and tissue samples. Casual contact will not spread the virus, however, the manners in which the virus spreads include:2

  • Touching your eyes, nose or mouth after coming into contact with the bodily fluids of an infected individual
  • Engaging in sexual contact with an infected person 
  • Consumption of breast milk from an infected mother 
  • Transmission through organ, bone marrow or stem cell transplantation, as well as blood transfusions 
  • During childbirth, an infected mother can transmit the virus to her baby either before or during delivery - the risk of transmission to the baby is higher if the mother contracts the infection for the first time during pregnancy 

Antiviral drugs for Cytomegalovirus

Many people do not notice that they are infected with CMV and therefore don’t seek treatment. The viral infection can improve without treatment within about 3 weeks.1

Currently, four main antiviral drugs are used to combat CMV: ganciclovir, valganciclovir, foscarnet, cidofovir.New drugs are still being developed to date.

Antiviral drugs play a critical role in both the prevention and treatment of CMV. They play a role in preventing infections in transplant recipients for both solid organ transplants and blood cell-related transplants. (hematopoietic stem cell transplants) Antiviral drugs are also used to treat active infections in persons presenting with a weak immune system. CMV retinitis is a severe form of CMV which occurs in the eyes often in people with advanced HIV/AIDS.3

Ganciclovir

Intravenous ganciclovir was one of the first-line treatments for CMV. One of the most compelling pieces of evidence for the drug’s efficacy was seen in 1987 where 55% of patients demonstrated significant clinical improvements after being treated with ganciclovir intravenously4. While studies have found a reduction in CMV infection with ganciclovir, it did not improve the overall survival benefits and was even associated with bone marrow suppression.5

Ganciclovir transforms into its active state through three cellular enzymes. The drug can target the virus while sparing healthy cells. The active form of ganciclovir accumulates more in cells infected with CMV, this contributes to its selectivity and effectiveness in treating the infection.6

Valganciclovir

Valganciclovir is favourable for long-term treatment of the virus. It can be taken orally and is often used in organ transplant recipients. One large-scale study found that 83.9% of CMV cases were effectively treated with valganciclovir when used as a preemptive measure. This treatment lasted longer compared to ganciclovir and it was considered safe, with no instances of treatment withdrawal due to side effects.7 Valganciclovir is transformed into ganciclovir inside our bodies. It works by slowing down the virus’s ability to make copies of its DNA.8

Foscarnet

Foscarnet is an antiviral that is used to treat CMV in patients who don't tolerate ganciclovir or have drug-resistant CMV. It works by disguising itself as part of the virus. When the virus tries to make more copies of itself, foscarnet sticks to the enzyme that facilitates the spread of the virus and stops it. The drug can affect our own cells, but we don't need very high doses of this treatment to treat the virus.9

Typically, foscarnet is administered through injection. There is evidence to suggest its efficacy in treating CMV in donor transplants. Some researchers have found that treating CMV with this drug is more effective when the amount of the virus circulating is lower. An advantage of foscarnet is limited kidney involvement.10

Cidofovir

Cidofovir was one of the first drugs approved for clinical use in CMV, The drug has been used for intravenous treatment of CMV in transplant recipients and patients with AIDS. Studies have found that when cidofovir was used to treat CMV in stem cell transplant recipients, patients responded well and results were comparable to those who received treatments of ganciclovir or foscarnet. This antiviral drug was just as effective as the standard treatments with a low number of patients experiencing side effects.11

Cidofovir acts like a roadblock, stopping a specific building block from getting added to the virus’s DNA. This interruption prevents the virus from extending its DNA chain and making more copies. Unlike other antiviral drugs, cidofovir doesn't need a special activation step from the virus to start working.12 

Challenges and considerations

Side Effects

Some of these antiviral drugs can cause changes to cells of the human body which can lead to the expression of side effects. Some of these may be common, but if you experience any severe side effects you should consult your doctor or visit A&E immediately. 

Ganciclovir:13

  • Nausea and vomiting
  • Diarrhoea or constipation 
  • Stomach issues: pain, belching, loss of appetite 
  • Changes in your ability to taste food 
  • Dry mouth, mouth sores 
  • Anxiety, depression 
  • Sweating, flushing 
  • Body ache, joint or muscle pain 

Valganciclovir:14

  • Changes in the colour of skin on your face 
  • Confusion - false beliefs, trouble thinking, hallucinations Issues with breathing (fast, irregular) 
  • Hive-like swelling on eyelids, lips, mouth, tongue or face 
  • Runny nose 
  • Seizures 
  • Sensations of tight chestedness 

Foscarnet:15

  • Changes in the frequency of urination or amount of urine  
  • Increased thirst (most common)
  • Chills, fever 
  • Convulsions, muscle twitching, tremors
  • Pain at the injection site
  • Numbness or pain in hands or feet 
  • Tingling around the mouth 
  • Tiredness and weakness

Cidofovir:16

  • Nausea or vomiting 
  • Diarrhoea 
  • Loss of appetite 
  • Headache 
  • Hair loss 
  • Sores on mouth, lips or throat 

Drug-Resistance

It is not uncommon to see that long-term usage of ganciclovir can lead to resistance. A recent study showed that taking ganciclovir for more than 8 weeks is associated with antiviral drug resistance, however, this effect was not seen in the 6-week course.17

Researchers can identify the resistance by looking for changes in the genetic material of the virus in two key genes: UL97 kinase and UL54 DNA polymerase. Many different types of changes can occur and not all of them make the virus resistant to the medicine. However, all the current antiviral drugs for CMV target the same part of the virus. If the virus becomes resistant to one of these drugs it might also be resistant to others.18

Several factors can increase the risk of drug resistance: 

  • Long term use
  • Not taking them correctly 
  • Having a type of transplant that increases vulnerability 

Doctors can try different strategies to treat resistant CMV, by increasing the dosage, using a combination of drugs or adding special immune cells that fight the virus.19

New drugs like maribavir, brincidofovir and letermovir target different parts of the compared to the traditional antiviral drugs. Letermovir is showing the most potential. Studies indicate little resistance in patients who have received the drug between 2018 and 202020. In a 2023 study, researchers noted that letermovir was just as successful in preventing CMV as valganciclovir. Furthermore, letermovir is now known to be less harmful to the bone marrow, and dosage doesn’t need to be altered relative to kidney function.21

Summary

In summary, the treatment landscape for cytomegalovirus has advanced significantly with the introduction of antiviral drugs. Ganciclovir, valganciclovir, foscarnet and cidofovir have proven effective in preventing and treating CMV infections particularly in transplant recipients and those with compromised immune systems. Despite their efficacy, the use of these drugs does not come without challenges as they may exhibit side effects and lead to drug resistance. Researchers are actively exploring new avenues, with promising candidates like letermovir showing potential in preventing CMV with fewer side effects. As we delve into evolving strategies for CMV management, the pursuit of innovative drugs offers hope for more targeted and efficient treatments, ultimately improving outcomes for individuals affected by this complex viral infection.

References

  • NHS. Cytomegalovirus (CMV). [Internet]. [Updated 2017; Cited 15 December 2023] Available from:  https://www.nhs.uk/conditions/cytomegalovirus-cmv/ 
  • Mayo Clinic. Common viral infection of babies and people with weakened immunity-Cytomegalovirus (CMV) infection - Diagnosis & treatment. [Internet] [Updated 23 March 2022; Cited 15 December 2023] Available from: https://www.mayoclinic.org/diseases-conditions/cmv/symptoms-causes/syc-20355358
  • Chen S-J, Wang S-C, Chen Y-C. Antiviral Agents as Therapeutic Strategies Against Cytomegalovirus Infections. Viruses [Internet] 2019 [Cited 15 December 2023];12(1):21. Available from: https://doi.org/10.3390/v12010021.
  • Erice A, Jordan MC, Chace BA, Fletcher C, Chinnock BJ, Balfour HH Jr. Ganciclovir Treatment of Cytomegalovirus Disease in Transplant Recipients and Other Immunocompromised Hosts. JAMA [Internet] 1987 [Cited 15 December 2023];257:3082–7. Available from: https://doi.org/10.1001/jama.1987.03390220080025.
  • Jerry Teng C-L, Wang P-N, Chen Y-C, Ko B-S. Cytomegalovirus management after allogeneic hematopoietic stem cell transplantation: A mini-review. Journal of Microbiology, Immunology and Infection. [Internet] 2021[Cited 15 December 2023];54:341–8. Available from: https://doi.org/10.1016/j.jmii.2021.01.001.
  • Matthews T, Boehme R. Antiviral Activity and Mechanism of Action of Ganciclovir. Clinical Infectious Diseases. [Internet] 1988 [Cited 15 December 2023]; 10:S490–4. Available from: https://doi.org/10.1093/clinids/10.Supplement_3.S490.
  • Len O, Gavalda J, Maria Aguado J, Borrell N, Cervera C, Miguel Cisneros J, et al. Valganciclovir as Treatment for Cytomegalovirus Disease in Solid Organ Transplant Recipients. Clinical Infectious Diseases. [Internet] 2008 [Cited 15 December 2023]; 46:20–7. Available from: https://doi.org/10.1086/523590.
  • Drugbank Online. [Internet] Valganciclovir. [Created 29 August 2007, Accessed 15 December 2023]. Available from: https://go.drugbank.com/drugs/DB01610 
  • Wagstaff AJ, Bryson HM. Foscarnet: A Reappraisal of its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Use in Immunocompromised Patients with Viral Infections. Drugs [Internet] 1994 [Cited 15 December 2023]; 48:199–226. Available from: https://doi.org/10.2165/00003495-199448020-00007.
  • Metafuni E, Chiusolo P, Sica S, Laurenti L, Bregante S, Van Lint MT, et al. Foscarnet treatment of cytomegalovirus infection in haploidentical or unrelated donor transplants. Bone Marrow Transplant. [Internet] 2018 [Cited 15 December 2023]; 53:1560–7. Available from; https://doi.org/10.1038/s41409-018-0200-y.
  • Yin Z, Xu N, Jiang L, Shi P, Fan Z, Huang F, et al. Cidofovir, a Choice for Salvage Treatment of CMV Infection in the Patients with Haploidentical Hematopoitic Stem Cell Transplantation. Blood [Internet] 2020 [Cited 15 December 2023]; 136:40–1. Available from: https://doi.org/10.1182/blood-2020-138685.
  • Lea AP, Bryson HM. Cidofovir: Drugs [Internet] 1996 [Cited 15 December 2023]; 52:225–30. Available from: https://doi.org/10.2165/00003495-199652020-00006.
  • MedlinePlus. [Internet] Ganciclovir.  [Updated 15 May 2016; Cited 15 December 2023] Available from: https://medlineplus.gov/druginfo/meds/a605011.html
  • Mayo Clinic. [Internet] Valganciclovir (Oral Route). [Updated 1 February 2024, Cited 15 December 2023] Available from: https://www.mayoclinic.org/drugs-supplements/valganciclovir-oral-route/side-effects/drg-20066642?p=1
  • Mayo Clinic. [Internet] Foscarnet (Intravenous Route). [Updated 1 March 2024; Cited 15 December 2023] Available from: https://www.mayoclinic.org/drugs-supplements/foscarnet-intravenous-route/side-effects/drg-20063973
  • MedlinePlus. [Internet] Cidofovir Injection. [Updated 15 November 2016]; Cited 15 December 2023] Available from: https://medlineplus.gov/druginfo/meds/a696037.html
  • Acquier M, Taton B, Alain S, Garrigue I, Mary J, Pfirmann P, et al. Cytomegalovirus DNAemia Requiring (Val)Ganciclovir Treatment for More Than 8 Weeks Is a Key Factor in the Development of Antiviral Drug Resistance. Open Forum Infectious Diseases. [Internet]  2023 [Cited 15 December 2023]; Jan 10:ofad018. Available from: https://pubmed.ncbi.nlm.nih.gov/36817745/ 
  • Hakki M, Chou S. The biology of cytomegalovirus drug resistance. Curr Opin Infect Dis [Internet] 2011[Cited 15 December 2023]; 24:605–11. Available from: https://doi.org/10.1097/QCO.0b013e32834cfb58.
  • El Chaer F, Shah DP, Chemaly RF. How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. Blood. [Internet] 2016 [Cited 15 December 2023]; 128:2624–36. Available from: https://doi.org/10.1182/blood-2016-06-688432.
  • Perchetti GA, Biernacki MA, Xie H, Castor J, Joncas-Schronce L, Ueda Oshima M, et al. Cytomegalovirus breakthrough and resistance during letermovir prophylaxis. Bone Marrow Transplant. [Internet] 2023 [Cited 15 December 2023]; 58:430–6. Available from: https://doi.org/10.1038/s41409-023-01920-w.
  • Limaye AP, Budde K, Humar A, Vincenti F, Kuypers DRJ, Carroll RP, et al. Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial. JAMA [Internet] 2023 [Cited 15 December 2023]; 330:33. Available from: https://doi.org/10.1001/jama.2023.9106.
This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Jessica Nicholson

Master of Neuroscience – MSc, University of Sussex

I have a BSc in Psychology with Neuroscience as well as an MSc in Neuroscience. I am passionate about bridging the gap between healthcare, science and the wider community. I have worked for the NHS as a youth research advisor and I also enjoy volunteering/support work with local charities that support the disabled community.

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