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Madeleine R. Heldman, MD, MS, discusses managing cytomegalovirus, including advances in CMV assessment and antiviral and immune strategies.

Clinical trial results over the past 5 years have enabled new approaches to cytomegalovirus prevention in transplantation settings, researchers wrote in their review of current and future strategies to prevent and treat CMV infections in transplants.

“Letermovir and maribavir are new antivirals for the prevention and treatment of CMV infections, respectively, and are safe alternativates to historical agents. Investigational strategies that enhance CMV immunity have potential to improve long-term CMV control in different transplant settings,” they added in Clinical Infectious Diseases.

However, the researchers advised that preventing and treating CMV infection is an important aspect of clinical care in solid organ and allogeneic hematopoietic cell transplantation, and more studies are needed to refine their use.

They reviewed recent advances in CMV risk assessment and progress in antiviral and immune-based strategies to prevent and treat CMV, emphasizing CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T-cells. They also summarized observational and interventional studies of commercially available CMV cell-mediated immunity assays.

Lead author Madeleine R. Heldman, MD, MS, spoke with Physician’s Weekly (PW) about the results of their review.

PW: For clinicians, what are the review’s key points?

Dr. Heldman: CMV is one of the most common infections in transplant recipients and causes a lot of anxiety for patients and clinicians. In the past 5 years, we have seen two new antivirals, letermovir and maribavir, become available for CMV prevention and treatment, respectively. These are oral drugs with fewer toxicities than historical antivirals.

While the advent of these novel agents is exciting, antivirals do not address the deficits in CMV-specific immune responses that underlie the predisposition to CMV infections after transplant. Vaccines, monoclonal antibodies, and virus-specific T cells are immune-based strategies that are actively being evaluated in clinical trials.

Why was it important to conduct this review?

The epidemiology of transplant recipients at risk for CMV is evolving. In solid organ transplant (SOT), CMV seronegative recipients of organs from CMV seropositive donors (D+R-) account for approximately 20% of all SOT recipients but for over 90% of cases of CMV disease (i.e., CMV infection that causes illness). The proportion of SOTs that are CMV D+R- has increased over the past decade and is projected to continue increasing if current trends continue.

In hematopoietic cell transplant (HCT), post-transplant cyclophosphamide (PTCy) is increasingly used for graft-versus-host disease prevention, and the landscape of CMV infections after PTCy will need to be explored. Commercial assays that measure CMV-specific cell-mediated immunity are becoming available, and clinicians should understand how their predictive values vary in different transplant populations.

Did the results you reviewed surprise you?

We discussed findings from recent studies that are not necessarily intuitive. Pre-emptive therapy (PET) and prophylaxis are established strategies for preventing CMV disease in SOT recipients. PET involves weekly CMV PCR surveillance and only initiating CMV antivirals for treatment at pre-defined viral load thresholds. Many centers favor using prophylaxis over PET in high-risk CMV D+R- SOT recipients, given the rapid kinetics of CMV replication in this population and theoretical concerns about the potential effects of asymptomatic CMV infection on long-term graft survival and outcomes.

We discussed a randomized clinical trial that compared PET to valganciclovir prophylaxis for the prevention of CMV disease in CMV D+R- liver transplant recipients. PET was actually superior to prophylaxis in preventing CMV disease in the first year after transplant. Immunologic studies suggest that the early, controlled DNAemia intrinsic to PET facilitates development of CMV-specific immune responses, which ultimately protects patients from late CMV infections.

What are your thoughts on advances in CMV risk assessment and treatment and differences in CMV management based on transplant type (solid organ vs. stem cell)?

The risks and benefits of any CMV prevention or treatment strategy differ considerably between SOT and HCT and by donor and recipient serostatus, immunosuppression, hematopoietic cell source and HLA matching (HCT), and organ type (SOT).

Another important difference between SOT and HCT is that HCT recipients may eventually develop a “normal” immune system (in the absence of relapsed disease or chronic graft versus host disease). SOT recipients require lifelong immunosuppression.

This means that antiviral prophylaxis for a fixed duration after HCT may be a sufficient “bridge” to immune reconstitution. In SOT, antiviral prophylaxis may simply delay inevitable CMV infection in some patients.

Are any strengths or limitations of the review especially noteworthy? 

The strengths and limitations of all interventions discussed in the review can differ considerably in different transplant populations. For example, CMV-specific cell-mediated immunity assays have better predictive value in CMV seropositive (R+) SOT recipients than CMV D+R- SOT recipients, although CMV D+R- patients have the highest CMV-related morbidity and could benefit most from accurate CMV immune assessments. PET was safe and efficacious in a randomized clinical trial in CMV D+R- liver recipients, but it has not been systemically evaluated in other D+R- SOT populations. Organ-specific factors and differences in immunosuppression between different organ groups preclude extrapolation to non-liver SOT populations.

What further research is needed?

Alleviating the financial toxicity and inconvenience of anti-CMV medications and laboratory testing is an important aspect of everyday patient care. Studies are underway that will assess the feasibility and accuracy of at-home blood collection for CMV PCR testing (eg, dried blood spot testing and self-venipuncture devices). These methods could facilitate tight CMV PCR surveillance for high-risk patients who live far from their transplant centers. Vaccines are another potential avenue toward reducing reliance on antivirals.

An ongoing randomized clinical trial studying a (non-live) MVA-vectored CMV vaccine in CMV seronegative liver transplant candidates will yield exciting data in the coming decade.

What additional comments would you like to share with clinicians?

 CMV management in transplant recipients is a multidisciplinary process. Successful CMV prevention and treatment requires physicians to work with pharmacists, transplant coordinators, and case managers to ensure access to antivirals and adherence to CMV monitoring schedules.