Current and Future Therapies for CMV
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:
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.
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
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