CMV stewardship need

Improvement is needed in the prophylaxis and treatment of CMV after SOT, making it a natural extension of the principles of antimicrobial stewardship to the immunocompromised host. The clinical issues and associated burden of CMV infection have been well described, and thr management of CMV after SOT is complex.^{Reference Kotton, Kumar and Caliendo18–Reference Atabani, Smith and Atkinson30} The drug of choice has a narrow therapeutic index, and alternatives require careful patient selection.^{Reference Kotton31–Reference Bonatti, Sifri, Larcher, Schneeberger, Kotton and Geltner33} Adding complexity is the central role of cell-mediated immunity in successful treatment of CMV, requiring immunosuppressive modification and increasing risk of rejection.^{Reference Asberg, Jardine and Bignamini5,Reference Rolling, Jorgenson, Descourouez, Mandelbrot, Redfield and Smith7,Reference Anglicheau, Lautrette, Scieux, Flamant, Morinet and Legendre34,Reference Myhre, Haug Dorenberg and Kristiansen36} Clinical suspicion for disease and timing after transplant also play an important roles.^{Reference Erdbrugger, Scheffner and Mengel37–Reference Browne, Young, Dunn and Matas42} The risk associated with inappropriate or mismanaged prophylaxis and treatment is significant and can have lasting impact on both patient and graft survival. Novel antiviral agents are few, and the incidence of CMV and GR-CMV continues to rise. Additionally, the population potentially impacted by CMV continues to expand as the number of patients receiving and living with SOTs grows daily.⁴³ The following sections describe the elements that we feel are essential to the development of a CMV stewardship initiative as well as potential challenges, opportunities and future directions, based on our center-specific experience with the creation of a CMV stewardship program.

Implementation of CMV guidelines adapted to local context by local experts

Consensus guidelines exist summarizing expert opinion and evidence-based treatment of CMV.^{Reference Kotton, Kumar and Caliendo18,Reference Razonable and Humar45} However, variations in patient populations and center-specific immunosuppressive protocols require local adaptation of these guidelines for a center-specific CMV stewardship protocol. Stakeholder and expert buy-in are paramount to providing consistent, evidence-based recommendations. Prophylaxis modalities must be selected to appropriately align with the patient population at each transplant center. For example, for centers with a local patient base, a central local laboratory, and a large seropositive population may be best suited for a preemptive monitoring (PEM)–based approach. In contrast, universal prophylaxis may be preferred at centers with an SOT population that is remote given the magnification of the challenges of PEM in this population. Another example highlighting local adaptation of consensus guidelines is the recent transition away from the use of secondary prophylaxis after treatment to a risk-based model. Our CMV stewardship team has been integral in incorporating this major shift in guideline-based practice through the creation of high-risk recurrence criteria (Table 1) and the implementation of these practices. Additionally, approaches to treatment thresholds, intravenous-to-oral transitions, the use of CMV cell-mediated immunity (CMI) assays and criteria for resistance testing should be outlined to avoid extraneous and expensive laboratory testing as well as potentially unnecessary drug utilization or hospital admission. These guidelines should be developed and intermittently reviewed for quality improvement opportunities by an identified champion group including transplant surgeons, medical transplant physicians, infectious disease physicians, and clinical pharmacists (ie, a CMV task force).

Table 1. Recurrence Risk Factor Screening Protocol^a

Note. CMV, cytomegalovirus; PCR, polymerase chain reaction; LLOQ, lower limit of quantification.

^a Adapted from Kotton et al^{Reference Kotton, Kumar and Caliendo18} as well as expert opinion from the CMV Task Force at the University of Wisconsin Hospital and Clinics.

Inclusion of institutional stakeholders

The CMV stewardship team should include a pharmacist and stewardship physician. The stewardship physician should be a transplant infectious disease physician, or physician team, with appropriate knowledge base and interest in the program and ability to respond quickly to the stewardship pharmacist for patient care guidance. This physician must receive adequate financial and protected worktime support to function in this role. Given the complexity of CMV stewardship, the pharmacist involved in the CMV stewardship initiative should have broad clinical knowledge of transplant pharmacology, including immunosuppressive medications and the care of the transplant population. Interest and experience in infectious disease are also needed because the interplay between immunosuppressive agents, antivirals, the immune system and viral replication kinetics is complex.

The CMV stewardship initiative, which incorporates antivirals and immunosuppressive agents, is unique in its scope. Therefore, guidelines and monitoring protocols must be endorsed by the transplant division and by key transplant stakeholders. The inclusion of these key players as active members of the stewardship team is paramount because decisions that could improve CMV infectious outcomes must be weighed against the potential impact on the allograft. With all transplant subspecialties being involved in creation and approval of the guiding documents, awareness of the program is increased, and disparities and disagreements in care can be avoided.

Time commitment and allocation of dedicated resources

Current literature describing CMV stewardship initiatives have focused on either treatment or prophylaxis of CMV, and interventions mostly focus on appropriate dosing of GCV derivatives.^{Reference Wang, Athans, Neuner, Bollinger, Spinner and Brizendine46,Reference Hensler, Richardson and Brown47} We believe that appropriate allotment of resources can expand the scope of CMV stewardship and thereby address the current clinical need.^{Reference Eid, Arthurs, Deziel, Wilhelm and Razonable48} When designing our center-specific initiative, we did not limit scope, which resulted in identification of a multitude of stewardship targets. As has been stressed in the creation of ASPs, allotment of dedicated resources is crucial to the success. Due to the complexity, time spent in pharmacist evaluation is significant, and previously conducted time studies of ASPs in immunocompetent patients may not be accurate or applicable.

Prospective audit and feedback and the EMR

Stewardship recommendations are best made at the time of patient assessment and ordering of the drug.² Prospective audit and feedback between care settings is challenging and requires mechanisms to track patients and to ensure therapeutic monitoring is present, timely, and includes key stakeholders. Utilization of the EMR for this function can streamline prospective audit and documentation in the medical record. At our institution, we have been able to successfully identify, enroll, and track patients with antiviral needs requiring stewardship by employing functionality provided in our base EMR. Through development of clear inclusion criteria for enrollment in the CMV stewardship program, transplant pharmacists in both the inpatient and outpatient setting can capture qualifying patients. An example of the inclusion–exclusion criteria used in our program can be found in Table 2. The pharmacist coordinates interventions using delegation protocols based on local guidelines and consults the transplant infectious disease physician for complex patients where the guideline and the protocol do not apply.

Table 2. Cytomegalovirus (CMV) Antiviral Stewardship Pharmacist Monitoring and Interventions

Note. RPh, pharmacist; WBC, white blood cell count; SOC, standard of care; LLOQ, lower limit of quantification; ANC absolute neutrophil count.

Interventions identified by the CMV stewardship pharmacist must be communicated to the care team in a timely fashion. Utilization of the EMR allows for rapid correspondence to the multidisciplinary care team while also allowing documentation in the patient chart. Challenges may arise at centers where transplant care is not centralized, and these should be addressed early in program development.

Dose optimization

A critical goal of CMV stewardship is ensuring appropriate dosing of VGC to avoid toxicity from overdosing, treatment failure, or viral resistance. Fluctuations in renal function early after transplant surgery make close monitoring and tracking of at-risk patients at regular intervals critically important.

Dose optimization goes beyond strict adherence to package insert dosing, which further highlights the need for a dedicated transplant pharmacist. Knowledge base and insight to anticipate ongoing changes in renal function, paired with overall risk of drug toxicity and risk of CMV infection are paramount. The pharmacist must be aware of potential limitations in manufacturer dose suggestions in patients of very large or small stature.

Finally, the risk–benefit of aggressive dosing must be weighed at important clinical transition points. Some studies suggest that rapid viral clearance kinetics are associated with improved outcomes of CMV infection and reduced rates of recurrence.^{Reference Humar, Kumar and Boivin28} Brief periods of aggressive dosing paired with immunosuppressive reduction may result in rapid clearance of initial viral load and may help patients with persistent viremia clear the virus, thus improving CMV outcomes. Further research is needed in this area.

Measuring performance

The impact of the CMV stewardship must be assessed at regular intervals, with a focus on quality improvement. Given the longitudinal nature of CMV treatment, the creation of monitoring programs will provide further insight into the prevention and treatment of CMV after SOT. Members of a CMV stewardship team will be poised to study unique aspects of CMV care and address unanswered questions regarding management. When designing the CMV stewardship initiative, the creation of electronic tools to allow for retrospective evaluation of practices, quality review, and care efficiency should be individualized to optimize care at each transplant center. Additionally, measurable outcomes are necessary to demonstrate value and ongoing support for the program.

It is unlikely that CMV stewardship will have the same immediate and significant impact in cost savings as the antibacterial efforts of ASPs in immunocompetent hosts.^{Reference Goff, Bauer, Reed, Stevenson, Taylor and West49} Identification of issues may falsely skew outcome data to reflect increases in CMV infection after program initiation. However, this will also eliminate the “low-hanging fruit” conundrum many ASPs face when trying to demonstrate need for ongoing stewardship. Reduction in CMV complications will result in improvement in patient and graft survival, and it could even improve national transplant program ratings.

Diagnostics

Improvement in interlaboratory variability in CMV viral load quantification are needed to improve comparability.^{Reference Kotton, Kumar and Caliendo18} Despite the introduction of the World Health Organization (WHO) international standard, PCR results can vary significantly between laboratories due to a number of factors including amplification target, extraction methods, probe, amplicon size, and other factors.^{Reference Fryer, Anderson and Minor50,Reference Hayden, Yan and Wick51} This variation results in diagnostic and clinical management challenges, particularly as they pertain to initiation and discontinuation of antiviral treatment. The CMV stewardship team can aid in the delineation of appropriate treatment and/or the need for repeat testing based on concomitant clinical factors. Additionally, the sensitivity of currently available molecular diagnostics assays varies. Laboratories have, with increasing frequency, highly sensitive assays with the ability to quantify CMV viral loads to 35 IU/mL. The clinical significance of these low-level values is unknown, and clinical concern varies based on specific patient factors such as serostatus at transplant, current immunosuppressive regimen, indication for testing and the presence of symptoms. These highly sensitive assays also complicate duration of treatment, particularly in light of guideline recommendations to end therapy at the achievement of a viral load less than the lower limit of quantification (<LLOQ). This change to a relatively nonspecific therapy transition point can lead to vast differences in treatment duration. These inconsistencies in practice can be improved with a CMV stewardship initiative.

Antiviral use

Transplant practitioners are acutely aware of the negative impact of CMV on patient and graft outcomes; therefore, they are often quick to treat a positive result. However, the risk of antiviral toxicity and exposure predisposing to resistance should factor into the treatment decision. Isolation of bacteria in culture should not result in reflex antimicrobial use, and detectable CMV replication does not always necessitate antiviral therapy. Reduction in unnecessary testing and surveillance outside guideline-endorsed practice could reduce inappropriate antiviral use and its consequences. Utilizing prospective audit, CMV stewardship initiatives can preemptively assess results of molecular diagnostic testing and provide guidance.

Immunosuppressive management

CMV infection after SOT is a result of the immunosuppressed state required to support the allograft. However, there is minimal literature describing how best to modify immunosuppression in the setting of CMV infection. Although some small studies have evaluated the effect of immunosuppressive reduction at time of infection,^{Reference Asberg, Jardine and Bignamini5,Reference Anglicheau, Lautrette, Scieux, Flamant, Morinet and Legendre34} no guidance is available on titration after infection resolution. CMV stewardship initiatives should focus on this aspect of CMV treatment and bridging current knowledge gaps.