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Current and Future Therapies for CMV

August 21, 2014

In high-income countries, treatment for CMV has generally been one of the following drugs:

  • intravenous ganciclovir (Cytovene)
  • an oral formulation of ganciclovir called valganciclovir (Valcyte)

In addition, sometimes the following drugs can also be used:

  • intravenous foscarnet
  • intravenous cidofovir (Vistide)

Although each of these drugs can sometimes be effective, they can cause side effects such as injury to the bone marrow (ganciclovir, valganciclovir and cidofovir) and severe injury to the kidneys (cidofovir and foscarnet).

Furthermore, all four drugs target the same enzyme (DNA polymerase) needed by CMV-infected cells to make copies of this virus. Strains of CMV that are resistant to ganciclovir, foscarnet and cidofovir are emerging. Therefore, safer and more potent therapies are needed.


Emerging Therapies for CMV

Here are examples of two emerging therapies for CMV:

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Letermovir

One promising drug in development is letermovir (formerly called AIC246). In a well-designed phase II clinical trial, letermovir, at a dose of 240 mg once daily for 12 weeks, was highly effective in preventing the appearance of CMV-related disease in people who had received transplanted bone marrow. Letermovir's safety was similar to placebo and there was no injury to the bone marrow or kidneys. Letermovir works in a way that is different from current CMV therapies. Specifically, it works by interfering with enzymes unique to CMV, called the terminase complex. This unique property of letermovir is perhaps one reason why side effects with this drug are generally not serious as there is no equivalent enzyme made by human cells. Letermovir's activity against this enzyme also explains why it can be effective against strains of CMV that are resistant to ganciclovir and cidofovir. Furthermore, letermovir is expected to have few interactions with other medicines. Letermovir is being developed by Merck & Co. and is currently undergoing phase III clinical trials.


Brincidofovir

Another emerging anti-CMV therapy is brincidofovir (formerly called CMX001), an analogue of cidofovir. By attaching cidofovir to fatty substances and making other changes, researchers have made a drug that, unlike its parent compound cidofovir, can be absorbed when taken orally. Importantly, levels of brincidofovir do not build up in the kidney. Brincidofovir was originally developed as a defence against the possibility of biological warfare with smallpox virus. However, this drug has potent activity in laboratory experiments against a range of viruses, including common herpes viruses (HSV-1 and HSV-2). In a well-designed phase II clinical trial, brincidofovir was able to significantly reduce the risk of developing CMV-related disease among participants who received bone marrow transplants. Brincidofovir needs to be taken only twice weekly, as this drug accumulates inside CMV-infected cells, resulting in prolonged anti-CMV activity. However, brincidofovir can also build up in cells lining the intestine and may cause some gastro-intestinal side effects. Brincidofovir is being developed by Chimerix, Inc. and is currently undergoing phase III clinical trials.


For the Future

Researchers have conducted a small and short study of valganciclovir in people taking HIV treatment and found that the drug, at a dose of 900 mg per day for eight weeks, was able to modestly reduce excess activation of the immune system. However, valganciclovir can injure the bone marrow, so long-term use of this drug needs to be balanced against any possible benefit.

Some Canadian CMV experts predict that if all goes well with the phase III studies of letermovir and brincidofovir now underway, and once these drugs are approved by regulatory authorities, doctors and researchers are likely to regain interest in conducting clinical trials to suppress CMV activity. Such trials might recruit HIV-positive people to explore the following possibilities:

  • assess changes in inflammation
  • attempt to reverse premature aging of the immune system
  • seek to reduce CMV's impact on cardiovascular disease


Resources

Canadian researchers point to CMV as a problem for the immune system -- CATIE News

CMV co-infection linked to increased risk of heart and stroke problems -- CATIE News


References

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  4. Hsue PY, Hunt PW, Sinclair E, et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS. 2006 Nov 28;20(18):2275-83.
  5. Savva GM, Pachnio A, Kaul B, et al. Cytomegalovirus infection is associated with increased mortality in the older population. Aging Cell. 2013 Jun;12(3):381-7.
  6. Terrazzini N, Bajwa M, Vita S, et al. A novel cytomegalovirus-induced regulatory-type T-cell subset increases in size during older life and links virus-specific immunity to vascular pathology. Journal of Infectious Diseases. 2014 May 1;209(9):1382-92.
  7. Barnes LL, Capuano AW, Aiello AE, et al. Cytomegalovirus infection and risk of Alzheimer's disease in older blacks and whites. Journal of Infectious Diseases. 2014; in press.
  8. Chemaly RF, Ullmann AJ, Stoelben S, et al. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. New England Journal of Medicine. 2014 May 8;370(19):1781-9.
  9. Griffiths PD, Emery VC. Taming the transplantation troll by targeting terminase. New England Journal of Medicine. 2014 May 8;370(19):1844-6.
  10. Kaul DR, Stoelben S, Cober E, et al. First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246. American Journal of Transplantation. 2011 May;11(5):1079-84.
  11. Marty FM, Winston DJ, Rowley SD, et al. CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. New England Journal of Medicine. 2013 Sep 26;369(13):1227-36.
  12. Quenelle DC, Lampert B, Collins DJ, et al. Efficacy of CMX001 against herpes simplex virus infections in mice and correlations with drug distribution studies. Journal of Infectious Diseases. 2010 Nov 15;202(10):1492-9.
  13. Hostetler KY. Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: current state of the art. Antiviral Research. 2009 May;82(2):A84-98.
  14. Hayden EC. Biodefence since 9/11: The price of protection. Nature. 2011 Sep 7;477(7363):150-2.



This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication CATIE News. Visit CATIE's Web site to find out more about their activities, publications and services.
 

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