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Every year, roughly 84,000 patients receive a hematopoietic stem cell transplantation (HSCT).1 For many, it’s their last hope for fighting off an advanced or refractory disease.2 However, cytomegalovirus (CMV) viremia is still a risk, occurring in 30%-70% of recipients.3

Presentation: From Viremia to Disease

In HSCT recipients, insufficiently controlled CMV viremia remains a considerable risk even with CMV medication.4 Viremia can develop into CMV disease any time after transplant.5

CMV disease can cause multiorgan disease, including pneumonia, hepatitis, gastroenteritis, retinitis, and encephalitis, and the mortality rate attributed to CMV disease in HSCT recipients can be as high as 60%.5,6 CMV pneumonia is the most serious manifestation of CMV disease in HSCT recipients, and can manifest with fever, nonproductive cough, and hypoxia.7

Risk Factors for Developing CMV Viremia

Serostatus is a significant risk factor for development of CMV in HSCT. Recipients who are seropositive for CMV (R+) are at the highest risk for developing CMV viremia. Donor positive, recipient negative (D+/R-) transplants are at intermediate risk, while D-/R- are at the lowest risk.8

Additional factors for developing CMV viremia include T-cell depletion, use of high-dose corticosteroids, and acute and chronic graft-vs-host-disease (GVHD).7

Late-onset CMV is a significant complication in HSCT.7 Those treated for CMV in the first 100 days after transplant are at risk for late-onset CMV. Cord blood transplant recipients who are CMV seropositive and those treated with corticosteroids or other systemic immunosuppressive agents for chronic GvHD are also at increased risk.9

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The Persistent Challenge of Refractory/Resistant CMV

Viremia rates refuse to go down? CMV that is refractory or resistant to treatment can lead to high morbidity and mortality rates, particularly in high-risk HSCT recipients.10

In a study of 488 HSCT recipients, 51% experienced refractory CMV posttransplant.11 In a separate study, HSCT recipients with refractory CMV reactivation showed higher rates of CMV disease (11.9%) than those without refractory CMV (0.8%).10

Defining the Problem

Definitions for resistant and refractory CMV can vary between clinical practice and published literature. Clinical trials have historically used the following definitions10:

  • DNA base pairs mutating Icon.

    Antiviral drug resistance Viral genetic alteration—assessed by genotyping—that decreases susceptibility to one or more antiviral drugs.

  • Refractory Icon

    Refractory CMV CMV viremia that increasesa after at least 2 weeks of appropriately dosed antiviral therapy.

    aMore than 1 log10 increase in CMV DNA levels in blood or serum and determined by log10 change from the peak viral load within the first week to the peak viral load at ≥2 weeks as measured in the same laboratory with the same assay.

In clinical practice, the suspicion of drug-resistant CMV infection is often based on suboptimal responses to antiviral agents, whether or not it is confirmed by laboratory testing and the identification of a known mutation by genotyping.10

When it comes to recognizing viremia and taking action, time is of the essence. One retrospective study of 174 allogeneic HSCT recipients found that faster clearance of CMV was associated with better survival.8

Risk Factors for Refractory/Resistant CMV

There are many factors which can contribute to resistant CMV in HSCT, including lower doses or longer duration of antiviral therapy, subtherapeutic CMV drug levels (due to inadequate drug absorption and bioavailability or oral prodrug conversion), poor patient compliance, active GVHD, rising CMV viral load, treatment with antithymocyte antibodies, and T-cell depletion.10

Refractory/Resistant CMV is a Threat to Survival

Refractory/resistant CMV corresponds with significant clinical challenges: protracted disease course, organ dysfunction, drug toxicities, recurrences, and a high mortality rate. In a recent study, recipients with refractory CMV reactivation showed a higher incidence of nonrelapse mortality (17.1%) than those without refractory CMV (8.3%). To make matters even more complex, second-line treatments for CMV often have significant toxicities. In one retrospective review of solid organ transplantations and HSCT with 39 patients, 51% of transplant recipients treated with a second-line antiviral experienced renal dysfunction.10,12

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The Compounding Harm of Neutropenia

CMV is just one front in the battle against posttransplant infection, but it is not an isolated fight. Because of its role in influencing the production of various cytokines and T-cell responses, CMV makes it more difficult for the body to fight off additional infections.13 Neutropenia caused by antiviral therapy aggravates that effect, leaving the body more vulnerable to bacterial and fungal coinfections, potentially leading to worse outcomes and increased treatment costs.7,14

Neutropenia can occur in about 30% of HSCT patients treated with antiviral therapy.14

A threat to survival

Historically, neutropenia is associated with worse outcomes in HSCT. Specifically, it has been shown to negatively impact overall survival, event-free survival, and nonrelapse mortality.15

Shield icon.

The Menacing Risk of Graft-Vs-Host-Disease

GVHD continues to be a significant factor in HSCT, with acute GVHD being shown to occur in up to 40% of HSCT recipients with matched related donors and 60% of recipients with unrelated donors.16 GVHD is a major cause of mortality and morbidity, and has been associated with impaired posttransplant quality of life.14 In one study of 130 patients who experienced severe acute GVHD after HSCT, survival rates were 62%, 49%, and 47% at 1, 2, and 3 years respectively.17

While GVHD is a threat even in the absence of CMV, it has also been shown to be a significant risk factor for developing CMV viremia and disease.7,14 Additionally, CMV may play a role in the development of GVHD, creating a bidirectional relationship.14

a bidirectional relationship between CMV and GVHD

The immunosuppressive effects of GVHD and the corticosteroids used to treat it may allow for the reactivation of CMV.14


Kidney Icon.

The Precarious Threat of Renal Dysfunction

Acute and chronic kidney diseases are common following HSCT and can lead to long-term effects and negative impacts on mortality and morbidity. HSCT-associated kidney injury can be multifactorial, with causes including conditioning chemotherapy, radiation, nephrotoxic medications, and GVHD.18 To further complicate management, antiviral dose adjustments often have to be made for renal impairment.12,19 This creates the difficult balancing act of managing CMV with renal dysfunction.

A dangerous cycle that increases the risk of resistance

The nephrotoxicity balancing act is a tricky one, as renal function must be monitored and dose adjustments are often made for renal dysfunction.5 However, the same lowered dosage that can help protect kidneys is a risk factor for resistance, in turn making CMV infection more difficult to treat successfully.20

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