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Refractory CMV in SOT
Strategies for Optimizing Antiviral Treatment of Refractory CMV Infections in Solid Organ Transplant Recipients

Released: July 31, 2025

Camille Kotton
Camille Kotton, MD, FIDSA, FAST
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Key Takeaways
  • Early viral load monitoring and clinical evaluation are key for identifying refractory cytomegalovirus (CMV) infections.
  • Treatment options for refractory CMV include high-dose ganciclovir, maribavir, or foscarnet, with selection guided by CMV DNAemia, clinical severity, and infection site.
  • Other considerations for treatment include results of resistance testing, optimizing immunosuppression, and adjunctive therapies such as intravenous immunoglobulin.

Identifying Refractory CMV Infections in SOT Recipients
The key to identifying refractory cytomegalovirus (CMV) infections in solid organ transplant (SOT) recipients is monitoring CMV DNAemia with weekly viral load testing after initiating treatment. Although we commonly see an increase in CMV DNAemia at Week 1 because of lysis of CMV from treatment, you should see improvement in clinical symptoms of CMV and a decrease in CMV DNAemia by Week 2. If you do not see improvement in these measures after 2 weeks of treatment, then you need to consider whether the patient might have refractory CMV infection. 

However, it is also important to look at the dosing of the antiviral you are using—commonly valganciclovir or intravenous ganciclovir— and make sure that you are dosing according to the patient’s kidney function. Sometimes persistently high CMV DNAemia or increasing CMV DNAemia while on treatment is because of inadvertent underdosing. This can be common, especially given the fluctuations in renal function among SOT recipients. So if the patient seems to be appropriately dosed and has been taking medications as directed and still has not demonstrated significant improvement by Week 2, refractory CMV infection should be considered.

The CMV guidelines also recommend CMV resistance testing to look for resistance mutations to the antiviral agents most commonly used for treatment and prevention of CMV. This can further inform second-line treatment for refractory or resistance CMV infections.

Treatment of Refractory CMV in SOT Recipients
For treatment of refractory CMV, the guidelines recommend using high-dose ganciclovir, 7.5-10 mg/kg IV every 12 hours, or switching agents to maribavir or foscarnet. The choice between maribavir and foscarnet largely depends on if there is evidence of central nervous system disease or retinitis. In those cases, maribavir should be avoided because it cannot reach those compartments very well. Also, if there is severe, life-threatening disease or very high viral load, I recommend foscarnet.

However, many patients with refractory disease have low to moderate viremia with mild clinical symptoms or are asymptomatic. For these patients, either maribavir or high-dose ganciclovir would be reasonable therapeutic choices. The guidelines do not recommend letermovir for treatment; it is recommended only for standard or secondary prophylaxis after management of resistant/refractory CMV with other antiviral agents.

Finally, “refractory” CMV is an umbrella term. Resistant CMV is a subset of refractory disease, in which the defined resistance mutation is found. But CMV resistance testing is not perfect. Sometimes resistance mutations can be missed, especially with Sanger sequencing. So both types are often grouped together as refractory/resistant CMV because resistance is less specifically defined for CMV. Calling it only refractory CMV or resistant CMV would exclude cases that could potentially be resistant but have not been shown to have that mutation.

Using Resistance Testing
Earlier I mentioned resistance testing to identify resistance mutations to the most commonly used antiviral agents, but what is the best way to use resistance testing while still ensuring timely initiation of treatment? In my experience, most of this testing is done in commercial laboratories with turnaround times of approximately a week or sometimes less. I find that this quick turnaround time renders resistance testing quite clinically useful, especially compared with when it used to take longer.

That being said, some programs do not have access to resistance testing, and in those settings, I recommend using the treatment algorithm found in the guidelines. Working through the algorithm, I recommend making the best choices with the information that you have, even though you do not have resistance testing data. For example, you may wish to use foscarnet or maribavir if patients have significant valganciclovir/ganciclovir exposure because you assume that they have resistance to that agent.

For resistance testing to work well, it is recommended that there be a CMV DNAemia of at least 1000 IU/mL. Resistance testing is relatively expensive, so I recommend avoiding it if there is very low CMV DNAemia, as it will likely return uninterpretable results.

Other Considerations for Treatment of Refractory CMV
Another important consideration in treatment of refractory CMV is optimizing immunosuppression—that is, working with the transplant team to see if there is any opportunity to improve the patient’s immune status. Is there any opportunity to reduce immunosuppression during treatment for refractory CMV?

In addition, sometimes we consider the use of other adjunctive therapies such as intravenous immunoglobulin or CMV immunoglobulin, which is now recommended in the guidelines in this setting. Leflunomide, artesunate, and mTOR inhibitors are other adjunctive therapies that are not recommended outside of clinical trials, given lack of proven efficacy.

Your Thoughts
What challenges do you commonly face in identifying and treating refractory CMV? Leave a comment to join the discussion, and if you want more, make sure to register and join us for our hybrid virtual and in-person symposium in conjunction with the World Transplant Congress 2025!

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