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Refractory CMV
A Roadmap for Managing Refractory CMV

Released: July 30, 2025

Marcus Pereira
Marcus Pereira, MD, MPH, FAST
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Key Takeaways
  • Multiple treatment options exist for managing refractory CMV, including high-dose ganciclovir, maribavir, and foscarnet.
  • Treatment choice must be tailored based on disease severity, patient characteristics, and practical considerations, such as availability for lab monitoring or ability to take oral medications.

Treatment of Refractory CMV in Solid Organ Transplant Recipients
The good news is that we have a couple of options for treatment of refractory cytomegalovirus (CMV) in solid organ transplant recipients these days, which is a major improvement from just 5-6 years ago. Let us list the possibilities that are generally mentioned in the guidelines. 

The first treatment option is to simply increase the dose of ganciclovir. The standard dose of ganciclovir is 5 mg/kg every 12 hours for someone with a normal creatinine clearance. So, for patients who have refractory CMV and who are asymptomatic, you could increase the dose of ganciclovir to 7.5-10 mg/kg every 12 hours. That is not commonly done because of the potential for drug-related toxicities, but it is an option.

The first 2 main options in terms of antivirals are maribavir and foscarnet, as reflected in the guidelines for treatment of refractory or resistant CMV.

Generally, the guidelines suggest that maribavir would be a suitable option for those who are minimally symptomatic or asymptomatic, with a moderate to low viral load of ≤50,000 IU/mL. Of importance, maribavir is an oral medication only, with no IV formulation, so candidates for maribavir must be able to take oral medication.

If patients have severe disease or their viral load is >50,000 IU/mL, are intubated for pneumonitis, have severe colitis, or cannot take any oral medications, then foscarnet would be a better initial option for treatment. However, foscarnet is IV only, with important potential toxicities that could limit its use.

If you do not want to use foscarnet for an extended period out of concern for toxicities, but you are concerned that maribavir is not going to be robust enough, a third and interesting strategy that some experts recommend is the step down approach—that is, starting patients on foscarnet and then transitioning into maribavir to finish treatment once symptoms have improved and the viral load has decreased, ideally to <5000 IU/mL. That hybrid approach is increasingly being adopted as well.

A fourth option, which is not an antiviral per se but can sometimes be used as adjunctive therapy, is CMV hyperimmune globulin. These are purified, CMV-specific IgG isolated from donors with high CMV-specific antibody titers that can be used to augment treatment with maribavir or foscarnet.

Considerations for Treatment of Refractory CMV
All the treatment options discussed so far have issues that are important to consider. 

For one, ganciclovir itself has really profound bone marrow suppressive adverse effects. Patients’ white blood cell count or even sometimes their platelets can drop significantly while receiving that drug. If that is already a standard complication, imagine what could happen on a high dose. Patients could develop more severe leukopenia or neutropenia much more rapidly. That really limits the use of high-dose ganciclovir.

Foscarnet is a very potent anti-CMV drug, but nephrotoxicity is a major problem. Up to one third of patients who receive foscarnet develop nephrotoxicity, with some even requiring dialysis. In addition, foscarnet has been associated with changes in serum electrolytes, and it requires a lot of monitoring. It can be a really tricky drug to manage. This also limits using it for outpatient treatment of refractory CMV, as it requires labs several times a week to be effectively or safely monitored.

One of the main considerations for maribavir, as I alluded before, is that it is only available as a pill. There is no IV formulation. It also has some minor drug interactions, in particular with calcineurin inhibitors, but those are easily managed and generally do not present a huge problem. The main adverse effect is dysgeusia, a disruption of the sense of taste where everything tastes a little bit more metallic. Other than that, maribavir is well tolerated, with a good safety profile. However, maribavir is not recommended for central nervous system (CNS) manifestations of CMV, like cerebritis or meningoencephalitis. It is also not recommended for ocular manifestations like CMV retinitis.

For CMV hyperimmune globulin when used as an adjunctive therapy, its main issue is cost, but it is generally well tolerated, with rare but managed infusion-related reactions.

Choosing the Right Treatment
With all these treatment considerations, how do you put this together? I think it all depends on the individual patient.

We have a sense that foscarnet is the most potent antiviral. If your patient is really sick, I think that is probably the drug to consider most strongly, as something that will treat the virus most aggressively and bring it under control very quickly. Obviously, you want to watch out for the toxicities, but those should not prevent you from using foscarnet when it is needed.

Maribavir is also very effective, but with a lower barrier to developing drug resistance. So, I would want to be careful using it in patients with a high viral load. As it is oral only, it is also not suitable for patients with severe gastric issues or diarrhea, nor is it suitable for patients with CNS or ocular manifestations of CMV.

Finally, if your patient is in somewhat of a gray area for treatment options, I would consider using the step down approach or using hyperimmune immunoglobulin as an adjunctive treatment.

Your Thoughts
What do you find most challenging about treating refractory CMV? How do you approach choosing a treatment for these patients? Let us know by leaving a comment below and sign up to attend our satellite symposium in person or online if you want to learn more!

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