Refractory or Resistant Cytomegalovirus in Solid Organ Transplant Patients: Overcoming Challenges

Solid organ transplantation (SOT) revolutionized the treatment of organ failure and is a new lease on life for many patients. However, immunosuppressive medications used to prevent organ rejection increase the risk for infections, including cytomegalovirus (CMV). While many antiviral drugs are effective in treating CMV, refractory or resistant infections remain a constant threat.

CMV in SOT

CMV is a herpesvirus that infects most people, usually remaining dormant in those with healthy immune systems. However, in SOT recipients CMV can reactivate and cause retinitis, encephalitis, pneumonia, colitis, and hepatitis.

Refractory and Resistant CMV Defined

Refractory CMV infection is defined as an increase by >1 log₁₀ CMV DNA levels in blood or plasma after at least 2 weeks of appropriately dosed antiviral therapy.

Resistant CMV infection is defined as the presence of a viral genetic mutation that decreases the susceptibility to antiviral medication. Mutations in the UL97 and UL54 genes that encode the viral kinase and polymerase respectively are associated with resistance. Important risk factors for drug-resistance in SOT include, prolonged subtherapeutic doses of antiviral drug, donor CMV positive/recipient CMV negative serostatus, intense immunosuppression, and lung transplantation.

The cornerstone of CMV management in SOT has been nucleoside analogue antiviral medications, including ganciclovir, valganciclovir, and foscarnet. They inhibit CMV replication by targeting viral DNA polymerase. While these drugs have proven effective, prolonged use can lead to the emergence of CMV resistance.

Challenges in Managing Refractory and Resistant CMV

Refractory or resistant CMV compromises patient outcomes and complicates clinical management. Key challenges include:

• Limited Treatment Options: The emergence of drug-resistant CMV strains narrows the potential for efficacious therapy.
• Adverse Effects: Many commonly used antiviral medications have significant toxicities, including myelosuppression and nephrotoxicity.
• Detection: Routing monitoring of CMV viral loads is essential for detecting drug-resistant strains. Clinical suspicion is warranted in patients with risk factors.

Potential Solutions

Addressing CMV in SOT patients requires a multi-faceted approach that include:

• Patient Education: Transplant patients have a lot to manage. Take time to explain to them what CMV is and symptoms of it.
• Prevention: Adequate antiviral drug dosing, reducing immunosuppression when possible, and limiting long-term exposure to antiviral therapy can reduce the risk of developing CMV resistance.
• New Antivirals: Recently, 2 new CMV antivirals have received FDA approval. Maribavir is a UL97 kinase inhibitor indicated for the treatment of post-transplant CMV infection or disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet. Letermovir is a CMV DNA terminase complex inhibitor indicated for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant and prophylaxis of CMV disease in adult kidney transplant recipients at high risk.

For more, check out the following CE activities below, expiring soon!

Utilizing a CDST for Resistant/Refractory CMV in Solid Organ Transplant Patients – RMEI

Utilizing a CDST for Resistant/Refractory CMV in Hematopoietic Cell Transplant Patients – RMEI

Optimizing Treatment of Resistant/Refractory CMV Infection in Solid Organ Transplant Recipients – RMEI

Tackling Treatment-Refractory and Drug-Resistant CMV in the Solid Organ Transplant Setting: A Care Team Forum® – RMEI

Incorporating New Therapies to Hone the Treatment of Resistant or Refractory CMV in the Post-SOT Setting: Proceedings from a Clinical Olympics – RMEI