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Introduction

In this year of intense focus on a highly infectious coronavirus, discussion of cytomegalovirus (CMV) might seem like an afterthought. However, for persons undergoing stem cell or solid organ transplant (SOT) procedures, appropriate management of CMV can often mean the difference between life and death.^1,2 Preventive and management strategies are based on the assessed risk by evaluating the serostatus of the transplant recipient and the donor.³ Despite advances in the diagnostic and therapeutic modalities for its management, CMV remains one of the most important pathogens affecting transplant outcomes. Research into prophylaxis and antiviral treatment of CMV is advancing, with newer therapies and experimental approaches under consideration.^4-6 Among the few clinical practice guidelines currently available, these statements may not discuss the most up-to-date agents or research findings.⁷

Hospital/health systems pharmacists are directly involved with infection control protocols, as well as medication administration and management in the preemptive care and treatment of CMV infections.^8,9 It is essential for pharmacists who practice in hospital/health system settings or work with high-risk patient groups to be aware of the latest strategies for the prevention and management of CMV infection or reactivation.

CMV Infection: Ubiquitous and Opportunistic

CMV is a genus of herpesvirus, of which human cytomegalovirus (HCMV, or HHV-5) is the most studied.¹⁰ Overall CMV prevalence in the U.S is about 50%, varying by age, location, and socioeconomic status.¹¹ According to the Centers for Disease Control and Prevention (CDC), nearly 1 in 3 children in the U.S. has already been infected with CMV by age 5, while more than half of adults have been infected by age 40.¹² In immunocompetent adults, CMV usually causes minimal symptoms or a subclinical presentation.¹² Primary infection may be asymptomatic or may cause a self-limited febrile illness.¹³ However, for patients with compromised immune systems or who are undergoing a transplant procedure, CMV seropositivity is a significant concern.^1,2 Distinctions between CMV infection and CMV disease are outlined in Table 1.^14,15

CMV lies latent in the bone marrow and is carried via monocyte/myeloid progenitor cells, with reactivation occurring in macrophages and dendritic cells. Its primary target cells are monocytes, lymphocytes, and epithelial cells.¹⁶ CMV infection can be a major cause of morbidity and mortality, associated with a broad range of diseases such as pneumonia, retinitis, gastrointestinal diseases, cognitive dysfunction, and vascular disorders.^10,15 Individuals whose immune functions are compromised or immature may be at risk for opportunistic infection related to CMV.⁴ Because of the long latency period, recurrent infection is a risk.⁴ Reactivation of latent CMV can damage organ tissues and trigger indirect immunomodulatory effects that increase risks such as graft rejection in recipients of organ or stem cell transplants.¹⁷

Populations at Risk for CMV

In the hospital, individuals at greatest risk include people receiving SOT or allogeneic (donor) hematopoietic stem cell transplant (HSCT), and those with immunodeficiency syndromes.⁴

CMV has several indirect effects stemming from its ability to modulate the immune system.¹³ CMV infection is associated with increased risk of other infectious complications such as bacteremia, invasive fungal diseases, and Epstein‐Barr virus‐mediated post‐transplant lymphoproliferative disorders.¹⁸ In transplant recipients, CMV infection is also associated with acute rejection and chronic allograft injury, including chronic allograft nephropathy (in kidney recipients), bronchiolitis obliterans (in lung recipients), and coronary vasculopathy (in heart recipients).^19-21 CMV has a tendency to invade the transplanted allograft in patients with SOT. Thus, CMV is likely to cause hepatitis in a liver recipient, nephritis in a recipient of a kidney transplant, and pneumonitis in a lung transplant recipient.¹³ A significant association between CMV infection and lower survival rates has been demonstrated in many studies.^17,21-23

Guidelines for SOT and HSCT recommend pre-transplant testing for CMV via serology for all patients to determine CMV‐specific immunity.^7,18 Methods of testing are illustrated in Figure 1.^18,24 Interpretation guidance from the CDC are summarized in Figure 2.²⁴

Presence of viremia in organ transplant recipients identifies those at greatest risk for CMV disease. For patients slated to undergo transplant, CMV risk categories are determined as follows (also illustrated in Figure 3).¹⁸

• Lowest risk for CMV disease: Recipient is CMV‐seronegative and receives an organ from a CMV seronegative donor (D–/R–)
• Moderate risk for CMV disease: Recipients who are CMV‐seropositive (CMV R+) are classified as moderate risk due to the presence of preexisting CMV‐specific immunity. Risk of infection is higher when the donor is also seropositive (D+/R+)—versus a CMV‐seronegative donor (D−/R+)—due to the possibility of superinfection with donor‐transmitted CMV.
• Highest risk for CMV disease: CMV‐seronegative recipient without preexisting CMV‐specific immunity receives a latently infected organ or graft from a CMV‐seropositive donor (D+/R−).

According to the guideline statement published in February 2019 by the American Society of Transplantation/Infectious Diseases Community of Practice, "The major risk factor predisposing a patient to the development of CMV disease after SOT is a qualitative (functional) or quantitative deficiency in global (nonspecific) and/or CMV‐specific immunity."¹⁸

CMV is challenging to prevent and treat because of high viral mutation rates and long latency.⁵ Antiviral drugs are the mainstays for the prevention of CMV infection and disease.²⁵ Currently available antiviral drugs for CMV infections include:^4,25

• nucleoside analogs that inhibit of viral DNA polymerase (ganciclovir, valganciclovir)
• nucleotide analogs (cidofovir)
• pyrophosphate analog (foscarnet)
• viral terminase inhibitor targeting CMV (letermovir)

While ganciclovir and valganciclovir were the primary drugs used to treat and prevent CMV for many years, these agents are associated with adverse drug reactions including leukopenia or neutropenia, nephrotoxicity, or antiviral resistance.²⁶ Among the more specific antiviral agents have been developed or are under investigation is letermovir, an oral agent that acts directly against CMV by inhibiting the viral terminase complex.²⁵ This agent has improved tolerability relative to other antiviral categories.^26,27 The direct mechanism of action rules out cross-resistance with other antiviral drugs.

Guidelines for CMV Management in Solid Organ Transplant Recipients

Any level of CMV infection is associated with increased risk of mortality in patients undergoing a transplant procedure.²⁶ Patients who are CMV seropositive who undergo HSCT or SOT are at high risk for CMV reactivation. In addition, patients who develop a new CMV infection post-transplant are at increased risk for transplant failure and death.²⁵ Use of prophylactic or preemptive antiviral therapy against CMV disease in transplant recipients is based on detection of CMV in the blood.²⁸ Without a prevention strategy, CMV infection and disease typically occurs during the first 3 months after SOT. Anti‐CMV prophylaxis can delay onset of CMV disease in these patients.^29,30

Antiviral Prophylaxis

Antiviral prophylaxis is recommended for at-risk transplant recipients to prevent CMV infection and disease after transplantation. Antiviral drugs approved for prophylaxis are listed in Table 2.^18,31 As of September 2020, valganciclovir and intravenous ganciclovir listed as the preferred agents for antiviral prophylaxis in adults undergoing SOT.¹⁸ Alternative drug options for antiviral prophylaxis are intravenous ganciclovir (requires vascular access) and high‐dose valacyclovir for kidney transplant recipients only. In selected patients (e.g., heart and lung, intestinal transplant recipients), immunoglobulin preparations are sometimes used adjunctively with antiviral drugs.

Comparative clinical trials have evaluated the efficacy of ganciclovir, valganciclovir, and valacyclovir prophylaxis in CMV. For example, in a randomized clinical trial of 372 patients receiving kidney, liver, pancreas, or heart transplant (D+/R− ), the rate of CMV disease was comparable between those receiving 3 months of oral ganciclovir or valganciclovir prophylaxis (17.2% valganciclovir vs 18.4% ganciclovir at 12 months).³⁵

Letermovir, a viral terminase inhibitor targeted toward CMV, was approved in 2017 for CMV prophylaxis after allogeneic hematopoietic stem cell transplantation.^36,37 This agent is under investigation for use in CMV prevention in high-risk (CMV D+/R–) kidney transplant recipients.³⁸ Letermovir is well tolerated in comparison to the other agents with the most common reported adverse events during clinical trials being gastrointestinal toxicity (diarrhea, nausea, vomiting), fatigue, headache, skin rash and peripheral edema.^37,39 Importantly, letermovir does not appear to have significant renal and hematopoietic adverse effects (e.g., nephrotoxicity or myelosuppressive effects).⁴⁰

Prevention of post-prophylaxis delayed‐onset CMV disease

With the use of prophylaxis against CMV, viral disease may occur with a delayed onset. The AST guideline statement recommends surveillance for delayed-onset disease by testing via QNAT at least once weekly for 3 months, to detect CMV replication after completion of antiviral prophylaxis.¹⁸ If DNA for CMV is detected above a predefined threshold, it should be preemptively treated with the recommended agents. It is important to counsel transplant recipients about the risk for post-prophylaxis delayed‐onset CMV disease, even though they may have received antiviral prophylaxis. AST guidelines also suggest that lymphopenia and impaired global and CMV‐specific T‐cell responses may be measured after antiviral prophylaxis is completed, which may help to assess the patient's risk of post-prophylaxis delayed‐onset CMV disease.¹⁸

CMV Management for Patients Undergoing Stem Cell Procedures

Managing resistant or refractory CMV infection or disease in patients with hematologic cancers remains an ongoing challenge. Allograft rejection, over-immunosuppression, and lack of CMV-specific immunity are factors that predispose patients to delayed-onset CMV disease.⁴¹ Although current U.S. guidelines are not available for CMV management in patients undergoing stem cell procedures, a frequently cited guideline statement based on the 2017 European Conference on Infections in Leukaemia (ECIL 7).⁷ The document reviews the data on the diagnosis and management of CMV in patients after HSCT and in patients receiving other types of therapy for hematological malignancies.⁷ These guidelines represented a shift in the approach to CMV because they were the first to strongly recommend the use of CMV prophylaxis in this patient population (Table 5).⁷

Since the ECIL 7 guideline statement was developed, further research studies have helped to inform and shape treatment of CMV for improved outcomes in stem-cell transplant recipients. Traditionally, many HSCT centers have favored pre-emptive therapy over prophylaxis. These centers use CMV polymerase chain reaction (PCR) to monitor CMV levels, and treat for CMV only when CMV PCR reaches a prespecified level. This decision is based in part on the fact that the older oral drug, valganciclovir, is associated with high risk for neutropenia in the HSCT population.²⁶ The availability of letermovir allows for broader use of prophylaxis while lowering the risk for hematologic toxicities. In the pivotal 2017 study of letermovir for HSCT prophylaxis, significantly fewer letermovir-treated patients had clinically significant CMV infection.³⁶

Ljungman and colleagues recently performed a mortality analysis of letermovir for prophylaxis of CMV infection in seropositive recipients of allogeneic HSCT.²³ This study updates the mortality analysis from the 2017 phase 3 HSCT prophylaxis trial.³⁶ In the updated mortality analysis, the hazard ratio for all-cause mortality was 0.58 at week 24 (95% CI, 0.35–0.98; P = .04) and 0.74 at week 48 (95% CI, 0.49–1.11; P = .14) (Figure 4).²³ The trial's primary endpoint was incidence of all-cause mortality through week 48 post-HCT among the subset of patients with or without clinically significant CMV infection through week 24 post-HCT. In the placebo group, all-cause mortality was significantly higher in patients with clinically significant CMV infection, despite the use of preemptive therapy, compared with those without a clinically significant infection (31.0% vs 18.2%, respectively). However, for patients who received letermovir, no mortality difference was observed between those with clinically significant CMV infection and those without.

When CMV infection did occur among letermovir-treated patients, it tended to be delayed (e.g., after completion of the 14-week prophylaxis regimen).²³ This delay could be beneficial because it enables the immune system to better handle CMV reactivation. Another trial conducted to evaluate the potential benefits of more prolonged letermovir prophylaxis (200 versus 100 days) showed similar reduced incidence of CMV reactivation and clinically significant disease at 200 days.⁴²

New Developments in CMV Research

Despite advances in CMV prevention, there are still cases of complex CMV syndromes that can be devastating for transplant recipients. Ganciclovir and valganciclovir have been the mainstays of prophylaxis and treatment for many years, but are not always effective and may cause cytopenia. Traditional options for treating resistant/refractory CMV (foscarnet and cidofovir) are associated with suboptimal virologic responses and frequent toxicity, notably nephrotoxicity.⁴³ There is a need for additional agents that lack the hematologic toxicities of ganciclovir/valganciclovir and the nephrotoxicity of foscarnet and cidofovir. Vaccines aimed at preventing CMV infection and reducing the severity of disease are under development.⁴⁴ Ideally, a vaccine should be able to prevent or modulate CMV replication and disease. Vaccine development is taking two main approaches: viral modification, and focus on individual antigens.⁴⁵ Thus far, trials of CMV vaccines have not yet panned out with significant reductions in infection rate or survival benefit.⁴⁶

Maribavir is an oral investigational anti-CMV drug that targets viral kinase UL97. This agent has been studied in patients undergoing HSCT, liver, kidney, and transplant and is currently the only agent specifically under development for treatment of resistant/refractory CMV.⁴⁷ Two former phase 3 studies did not lead to statistically significant outcomes, but it was likely because the lowest dose was used.⁴⁸ A multicenter, phase 2, three-arm blinded trial of 3 maribavir doses in 120 patients with resistant/refractory CMV who were undergoing either SOT or HSCT.⁴⁸ Results were similar across all doses and showed a two-thirds response rate in terms of clearing viremia. The investigators noted this was an encouraging result considering this patient group had failed prior therapies. A 35% recurrence rate was seen, but is not surprising because this is often a feature of resistant/refractory CMV. Studies show maribavir lacks major organ toxicities; minor side effects include nausea and persistent dysgeusia.^49,50 A phase 3 trial in resistant/refractory CMV is underway, with a 2:1 open-label randomization to maribavir versus investigator-assigned therapy (e.g., foscarnet).^51,52

How Are Pharmacists Involved in CMV Management?

Because developments in CMV continually affect management recommendations, pharmacists who are engaged in management of CMV need to be aware of the most recent data on antiviral treatment and prophylaxis. Studies have shown that hospital pharmacists play an important role in containing and managing CMV.

Researchers from Cleveland Clinic evaluated the impact of a pharmacist-driven antimicrobial stewardship intervention targeting CMV viremia among 185 adults who underwent SOT and received antiviral therapy.⁸ Pharmacist intervention consisted of CMV DNA surveillance and notification and recommendations for optimizing drug therapy at the time of notification. Compared with usual care, significantly fewer patients in the intervention group reached a CMV viral load of >10,000 IU/mL immediately prior to treatment (10.6% vs 27.3%; P = 0.004), and a significantly greater proportion of patients in the intervention period achieved CMV eradication at 21 days (84.5% vs 71.7%; P = 0.038). Other benefits to the pharmacist intervention program included a greater rate of initiation of antiviral treatment within 5 days of the first quantifiable CMV DNA result and a reduce time to CMV eradication.⁸ The authors concluded, "Together, these findings suggest a potential role for pharmacist involvement in CMV surveillance and treatment optimization in ambulatory SOT recipients."

In another study, researchers at Duke University School of Medicine studied pharmacist-administered patient assistance programs (PAP) to determine whether early identification and enrollment could prevent CMV-related events in patients receiving kidney or pancreas transplants.⁹ In this retrospective analysis, 97 patients were evaluated; 39 who received valganciclovir through the PAP program and 58 who received usual care (CMV monitoring with preemptive QNAT. The incidence of CMV viremia was lower in the PAP group (12.8% vs 36.2% for usual care; P = .021). No significant differences were observed in CMV syndrome/disease, acute rejection, graft loss, or death between the groups. Furthermore, a cost-benefit analysis showed that hiring a full time pharmacy employee for the PAP was cost beneficial for the institution, showing health system savings of approximately $3,800 per case of CMV viremia prevented. These authors concluded, "Early identification and enrollment of patients in PAPs reduces the incidence of CMV viremia,” and that “Pharmacists play a crucial role in this process."⁹

"Early identification and enrollment of patients in [patient assistance programs] reduces the incidence of CMV viremia. Pharmacists play a crucial role in this process."

These findings demonstrate the impact of pharmacist involvement in CMV surveillance and treatment optimization in patients at risk for CMV infection. It is essential that pharmacists have the most up-to-date information and recognize how to implement services such as these in their institution.

Conclusion

Hospital pharmacists play an important role in containing and managing CMV. Studies have demonstrated a significant impact of pharmacist involvement in CMV surveillance and optimizing treatment in patients at risk for CMV infection. It is essential that pharmacists have the most up-to-date information and recognize how to implement services such as these in their institution. Pharmacists need to be aware of overall monitoring, prophylaxis, and treatment approaches, as well as new developments that may have occurred after publication of CMV guidelines. While new developments in CMV affect management recommendations, pharmacists who are engaged in management of CMV need to be aware of the most recent data on antiviral treatment and prophylaxis.

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