This activity is supported by an educational grant from Genentech.

A Review of Recent Research Updates in CMV

This educational activity is jointly sponsored by American Academy of

CME, Inc and Spire Learning.

This activity is supported by an educational grant from Genentech.

Release Date: April 15, 2012 Expiration Date: April 15, 2013

Target Audience • Transplant physicians and surgeons • Transplant pharmacists • Transplant coordinators and nurses

Learning ObjectivesAfter participating in this educational activity, participants should be better able to: 1. Assess the clinical implications of results from recently released studies investigating CMV prophylaxis, preemptive strategies, monitoring, treatment, and resistance management 2. Apply new evidence-based findings related to CMV prophylaxis, preemptive strategies, monitoring, treatment, and resistance management to their practices

Faculty AuthorRaymund R. Razonable, MDProfessor of MedicineCollege of MedicineMayo ClinicRochester, MN

Educational Planning Committee:Atul Humar, MDAssociate Professor, Department of MedicineDirector of Transplant Infectious DiseasesUniversity of AlbertaEdmonton, Alberta, Canada

Independent ReviewerEmily A. Blumberg, MDProfessor of MedicineDepartment of MedicineUniversity of Pennsylvania School of MedicinePhiladelphia, PA

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Table of Contents

CME/CE Information 1Faculty Biography 3Introduction 41. Prevention of CMV Disease 42. Ganciclovir Resistance 113. Monitoring and Treatment 134. Improving Outcomes: The Indirect Effects 145. Future Directions 156. Summary 16References 17

A Review of Recent Research Updates in CMV

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ACCREDITATION/CREDIT STATEMENTSThe estimated time to complete this educational activity is: 1.25 hours.There is no fee to participate in this activity.

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American Academy of CME, Inc designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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American Academy of CME, Inc, designates this educational activity for 1.25 contact hours.

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The Accreditation Program of the American Nurses Credentialing Center is interested in the opinions and perspectives of the participants in accredited continuing nursing education activities, particularly those perspectives related to the presence of perceived bias* in the continuing education. For this reason, we are now providing a toll-free telephone number. Participants may access this number at any time to: • Tell us of any noted bias or conflict of interest in the education • Tell us of any concerns, compliments, or opinions • Tell us of a great experience • Tell us of an unpleasant experience • Tell us your thoughts on the process

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To contact the Academy, e-mail jjuchniewicz@academycme.org.

DISCLOSURE STATEMENTSAll faculty, planners, editors, and others who are in a position to control content are required to disclose any relevant relationships with any commercial interests related to this activity. The existence of these interests or relationships is not viewed as implying bias or decreasing the value of the presentation. All educational materials are reviewed for fair balance, scientific objectivity, and levels of evidence.

Faculty AuthorRaymund R. Razonable, MDGrant recipient/research support: Genentech (PI) and Roche (PI); funds paid to his institution.

In this monograph, he discusses the non–FDA-approved or investigational use of diagnostics for CMV infection, the CMV gB/MF59 vaccine, the use of valganciclovir prophylaxis for liver transplant recipients, and alternative treatments for CMV disease, including valganciclovir, foscarnet, cidofovir, maribavir, CMX001, AIC246, and cyclopropravir.

Independent ReviewerEmily A. Blumberg, MDData Safety Monitoring Board: Chimerix (CMV related), Pfizer (not CMV related). Event Adjudication Board: Novartis (not CMV related)

Educational Planning CommitteeAtul Humar, MDAdvisory board – for scientific information: Astellas Pharma US. Grant recipient/research support: Roche (PI); funds paid to his institution.

John JD Juchniewicz, MCIS, CCMEP; Kathleen Hogan, RN, BSN, CCTC (transplant coordinator planner); and Natalie Kirkwood, JD, BSN, RN (nurse planner) Nothing to disclose

Faculty Biography

Raymund R. Razonable, MD Raymund R. Razonable, MD, is Professor of Medicine at the College of Medicine at the Mayo Clinic in Rochester, Minnesota. He also serves as Chair of Transplant Infectious Diseases, Associate Chair for Faculty Development, and Associate Program Director of the Infectious Disease Fellowship Program in the Division of Infectious Diseases at the Mayo Clinic. Dr Razonable received his medical degree from the Far Eastern University Institute of Medicine in Manila, Philippines. He completed his internship and residency at Beth Israel Medical Center in New York City, followed by a fellowship in infectious diseases at the Mayo Graduate School of Medicine.

Dr Razonable’s clinical interests include transplant and orthopedic infections and infections in immunocompromised hosts. His research addresses antiviral therapeutics, immunovirology, and transplant infections. He has authored more than 100 peer-reviewed articles, 22 book chapters, and more than 100 abstracts on these topics, and he has given numerous presentations at regional, national, and international meetings. Dr Razonable is also an editor for Transplant Infectious Disease, and he serves on the editorial boards of several respected journals.

A recipient of many awards and honors throughout his career, Dr Razonable was inducted as a Fellow of the Infectious Diseases Society of America in 2011. He is also a member of several other professional societies, including the American Medical Association, American Society for Microbiology, American Society of Transplantation (AST), AST Infectious Disease Community of Practice, International Immunocompromised Host Society, and The Transplantation Society.

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Educational Planning Committee (cont’d)Christine KociendaShareholder (spouse/partner): Johnson & Johnson, Procter & Gamble

Jeanne Prater Shareholder (spouse/partner): Johnson & Johnson; Employee (spouse/partner): Novo Nordisk

Jaime Symowicz, PhD, A. Scott Mathis, and Gregory ScottNothing to disclose

LEVELS OF EVIDENCE Levels of evidence are provided for any patient care recommendations made during this educational program.

Level A (randomized controlled trial [RCT]/meta-analysis)

Level B (other non-RCT studies)

Level C (consensus/expert opinion)

Each rating is applied to a single reference in the presentation, not the entire body of evidence on the topic.

The opinions expressed in this educational activity are those of the faculty and do not represent those of the Academy, Spire Learning, or the American Nurses Credentialing Center’s Commission on Accreditation. This activity is intended as a supplement to existing knowledge, published information, and practice guidelines. Learners should appraise the information presented critically and draw conclusions only after careful consideration of all available scientific information.

INSTRUCTIONS FOR CLAIMING CREDIT Please see the paper-based activity posttest and evaluation inserted in this monograph. You may also complete the posttest and evaluation online at http://tinyurl.com/TRANSPLANTAZ.

INTRODUCTION

Despite remarkable improvements in the diagnosis, prevention, and treatment of cytomegalovirus (CMV), it remains a significant infection that impacts the outcome of patients undergoing solid organ transplantation. Not only does CMV cause significant morbidity and increase the risk of mortality, but it also causes clinical disease and has other indirect effects that contribute to increased costs of solid organ transplantation. This monograph provides updates on the latest information on CMV disease after solid organ transplantation. Information gathered from peer-reviewed literature published in 2010-2011 and from recent meetings of the International Congress of the Transplantation Society and the American Transplant Congress was reviewed. From this extensive and contemporary literature review, the most noteworthy articles on CMV were selected for this update. The topics to be discussed in this review include (1) prevention of CMV disease, with special emphasis on the benefits and risks of extended CMV prophylaxis and a comparison of preemptive therapy versus antiviral prophylaxis, (2) CMV monitoring and treatment, and (3) CMV resistance.

1. PREVENTION OF CMV DISEASE

1.a. Antiviral ProphylaxisAntiviral prophylaxis is the strategy of preventing CMV disease after transplantation by administering antiviral drugs to transplant patients at risk of CMV disease. Over the years, the drugs that have been used for this strategy include valacyclovir (for kidney transplant recipients only), oral ganciclovir, and valganciclovir. Currently, valganciclovir is the most commonly used drug for this purpose. Antiviral prophylaxis is generally given for at least 3 months after transplantation, although the optimal duration has not been defined, and, as discussed in this review, it may need to be prolonged for lung transplant recipients and high-risk CMV D+/R- solid organ transplant recipients.1

1.a.1. Kidney Transplant RecipientsCMV D+/R- solid organ transplant recipients who receive 3 months of antiviral prophylaxis remain at increased risk of CMV disease. The onset of CMV disease is often delayed and usually occurs during the first 3 months after completion of antiviral prophylaxis. Because of the high incidence of late-onset CMV disease in CMV D+/R- solid organ transplant recipients, and because it continues to negatively impact transplant outcomes, there was a need to better define a better, if not optimal, duration of antiviral prophylaxis.

The IMPACT (Improved Protection Against CMV in Transplant) trial addressed the optimal duration of antiviral prophylaxis. This trial was an international phase III, multicenter, randomized, double-blind, placebo-controlled trial of valganciclovir in high-risk adult CMV D+/R- kidney transplant recipients.2 The study compared the standard 100 days versus a proposed 200 days of valganciclovir prophylaxis. The dose of valganciclovir was 900 mg once daily, and it was adjusted based on renal function. The objective of the study was to determine if CMV disease within 1 year after transplantation was reduced by extending valganciclovir prophylaxis from 3 to 6 months. The secondary endpoints included survival as well as the proportion of patients with CMV viremia, biopsy-proven acute rejection (BPAR), graft loss, opportunistic infections, and posttransplantation diabetes mellitus.

A total of 326 CMV D+/R- kidney transplant patients were randomized in the IMPACT trial, and the baseline characteristics were well balanced between the two groups. The experimental group received 200 days of valganciclovir prophylaxis, whereas the standard group received 100 days of oral valganciclovir prophylaxis followed by 100 days of placebo. A total of 76.9% of the 200-day group and 56.6% of the 100-day group completed the course of therapy. The primary endpoint is shown in Figure 1. CMV disease at 12 months, which was primarily manifested as CMV syndrome (97.6% of cases), occurred significantly less frequently in the 200-day group (16.1%) than in the 100-day group (36.8%, P<0.0001). Likewise, the time to onset of CMV viremia (viral load >600 copies/mL), as shown in Figure 2, was significantly delayed in the 200-day group compared with the 100-day group (P<0.001). Extended prophylaxis also significantly reduced the incidence of CMV viremia and disease at 6, 9, and 12 months after kidney transplantation (for example, the incidence at 12 months was 37.2% in the 200-day group vs. 50.9% in the 100-day group, P=0.015); it also reduced the incidence of opportunistic infections but did not significantly affect BPAR, allograft loss, or posttransplantation diabetes mellitus (Table 1).

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In a subsequent study of patient outcomes at 2 years after transplantation, the incidence of CMV disease remained significantly lower in the 200-day group (21.3%) than in the 100-day group (38.7%, P<0.001). Beyond the first year after transplantation, there were 7 additional cases of CMV disease in the 200-day group whereas there were only 3 additional cases in the 100-day group.3

Another study reported an even higher rate of late-onset CMV disease despite 6 months of valganciclovir prophylaxis.4 In one center, the incidence of CMV infection in adult CMV D+/R- kidney transplant recipients who received 6 months of prophylaxis with a 900-mg daily dose

These studies raise the issue of appropriate dosing when valganciclovir is administered as prophylaxis. Although the recommended dose of valganciclovir for prophylaxis is 900 mg once daily, many transplant centers that are administering a “mini-dose” of valganciclovir (450 mg) demonstrate similarly good outcomes, which is evidence that there is variation in dosing the agent; thus, the optimal dose of valganciclovir for D+/R- recipients remains controversial.5-7 A prospective study comparing 450- and 900-mg doses of valganciclovir to address this controversial issue has not been performed. However, a retrospective multicenter study of

of valganciclovir was 37%.4 In this study, late-onset primary CMV infections developed in a median of 244 days. Most of these CMV-infected patients (43/47) were clinically symptomatic (hence they were considered to have late-onset CMV disease), and their disease manifested with fever (N=28), gastrointestinal symptoms (N=24), respiratory tract symptoms (N=12), or hepatic dysfunction (N=6). Recurrent CMV infection further occurred in 19% of those patients.4 In the context of the IMPACT trial, these results suggest that, similar to 3 months of prophylaxis, 6 months of therapy may simply delay the onset of CMV disease,2,3,4-6 which raises a legitimate concern because it now occurs at a point when patients are no longer monitored as frequently.3

In an effort to reduce the cost, adverse effects, and other toxicities associated with full-dose valganciclovir dosing, several smaller studies evaluated the efficacy of lower-dose valganciclovir (“mini-dosing”) prophylaxis in CMV D+/R- kidney transplant recipients. These studies reported an incidence rate of 18.1%-27.5% of late-onset CMV disease among CMV D+/R- kidney transplant recipients who received 6 months of prophylaxis with a 450-mg daily dose of valganciclovir.5,6

In a study from the University of Illinois, extending prophylaxis with valganciclovir (450-mg daily) from 3 months to 6 months in CMV D+/R- kidney transplant recipients reduced the incidence of CMV disease from 32.5% to 27.5%, and, as expected, the median time to onset of CMV disease was delayed from 2.4 months to 7.1 months.5 In another study from the University of Michigan, CMV D+/R- kidney or kidney/pancreas transplant patients received prophylaxis with valganciclovir (450-mg daily) for 6 months.6 At the 1- and 2-year follow-ups, the incidence of late-onset CMV disease was 11.5% and 18.1%, respectively. The risk factors for the development of late-onset CMV disease were use of rabbit antithymocyte globulin (hazard ratio [HR], 2.91; 95% confidence interval [CI], 1.15-7.61; P=0.021) and older donor age (HR, 1.03; 95% CI, 1.01-1.06; P=0.016). During the follow-up period of 3.2 years, the occurrence of late-onset CMV disease was associated with death-uncensored graft loss (HR, 2.95; 95% CI, 1.18-7.2; P=0.025).6

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Figure 1

Figure 2

high-risk renal transplant recipients compared a 450-mg with a 900-mg daily dose of valganciclovir for 6 months.7 Patients were comparable with regard to clinical characteristics and patient demographics, including use of antithymocyte induction and maintenance immunosuppression. The 12-month incidence of CMV disease was 24.3% in the 900-mg group and 14.6% in the 450-mg group (P=0.068). It is of interest that resistant CMV disease occurred in 15.4% and 0%, respectively (P=0.126). The white blood cell count was significantly higher at months 5 and 6 in the group taking 450 mg of valganciclovir, but the rates of myelosuppression that led to discontinuation of valganciclovir prophylaxis were not significantly different.7

A recent meta-analysis also evaluated 12 trials (N=1,543) in which a 900-mg daily dose of valganciclovir was administered to kidney and other solid organ transplant recipients and compared this to 8 trials (N=1,531) in which a 450-mg daily dose was administered to these transplant recipients.8 Overall, the meta-analysis found that, compared with controls (those who received ganciclovir or a preemptive strategy), the relative risk of CMV disease was 1.06 (95% CI, 0.64-1.76) with a 900-mg daily dose of valganciclovir and 0.77 (95% CI, 0.49-1.18) with a 450-mg daily dose of valganciclovir. However, the relative risk of leukopenia was 5.24 (95% CI, 2.09-13.15; P=0.004) and 1.58 (95% CI, 0.96-2.61; P=0.07), respectively. When 900 mg of valganciclovir was compared with 450 mg in an indirect adjusted analysis, the risk of CMV disease was similar (odds ratio, 1.38; 95% CI, 0.84-2.25), but the risk of leukopenia was significantly increased with a 900-mg dose (odds ratio, 3.32; 95% CI, 1.76-6.26; P=0.0002). It is of interest that the meta-analysis showed that the risk of acute rejection increased with a 900-mg dose of valganciclovir compared with a 450-mg dose (odds ratio, 2.56; 95% CI, 1.5-4.53; P=0.0005).8 The major concern with “mini-dosing” of valganciclovir is the risk of drug resistance, which has been demonstrated to be more common among high-risk patients who received the lower dose of valganciclovir.9 Indeed, current guidelines advise against using a “mini-dosing” strategy, especially for high-risk CMV D+/R- transplant recipients, mainly because of the risk of ganciclovir resistance.1

Current guidelines recommend that CMV D+/R- kidney transplant recipients receive prophylaxis with a 900-mg once-daily dose of valganciclovir for 3-6 months after transplantation.1 One of the major concerns with extending the antiviral prophylaxis to 6 months was an increase in adverse drug effects, mainly myelosuppression. Indeed, in the IMPACT trial, the incidence of leukopenia was higher in the 200-day group than in the 100-day group (38% vs. 26%). In a study of the safety population, which evaluated adverse effects during days 101 and 200, when one group was receiving placebo and the other group was receiving valganciclovir, the incidence of leukopenia was 19% in the valganciclovir group and 4% in the placebo group.2 This risk of myelosuppression has been demonstrated by other investigators in other studies.7,8 Finally, in the IMPACT study, the incidence of CMV-related hospitalizations was higher (20.8%) in the 100-day group than in the 200-day group (10.4%), although the overall number of hospitalizations was similar between the two groups.2

The higher risk of myelosuppression with prolonged valganciclovir prophylaxis was not due to changes in the pharmacokinetics of ganciclovir. In the IMPACT trial, the pharmacokinetics of ganciclovir was stable whether valganciclovir was given for 100 days or 200 days and produced exposure in the desired range of 40-60 µg h/mL for most patients.10 The myelosuppression may be directly related to ganciclovir drug levels,11 and thus valganciclovir dosing should be adjusted based on renal function. One study compared the Modification of Diet in Renal Disease (MDRD) equation with the Cockcroft-Gault (CG) equation for determining dosing strategy and found that the MDRD equation led to underdosing in 38%-50% of patients with a creatinine clearance ≥60 mL/min compared with the CG equation.12 Hence, the CG equation is recommended for determining valganciclovir dose adjustment.12

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Table 1

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Finally, physicians and patients are concerned that extending valganciclovir prophylaxis to 6 months will lead to higher costs. To address this issue, the IMPACT investigators performed an economic analysis of this strategy.13 For this analysis, an economic model was created for 10,000 D+/R- kidney transplant recipients based on the first year of results of the IMPACT trial2 and projected out to 5 and 10 years using available literature. The investigators used a cohort Markov model, which accounts for different health states over time and quality-of-life differences affected by changes in health status. The model assumed that a reduction in CMV disease would result in a short- and long-term reduction in costs of care. The short-term reduction would reflect reduced CMV-related complications, and the long-term reduction would reflect differences in graft failure.

From the perspective of the United States payer, only direct medical costs were considered, whereas indirect costs, such as lost productivity, were not included. Quality of life was assessed using utility weights for different health states (where 1 corresponds to perfect health and 0 corresponds to death) and measured by quality-adjusted life years (QALYs). Model inputs included prophylaxis, presence or absence of CMV disease, post-CMV events, acute rejection preceding or following CMV disease, graft failure, and death. Costs and quality-of-life values were assigned to each model input.13 The final model, demonstrated in Table 2, indicates that although the costs are slightly higher for the 200-day prophylaxis group, the QALY was also increased, resulting in an incremental cost-effectiveness ratio of $14,859 per patient. This is considered cost effective because it is less than the generally recognized threshold of $50,000/QALY. Over 10 years, the use of 200-day prophylaxis was considered more cost-saving than the use of 100-day prophylaxis by $733 per patient.13 These data provided economic justification for extending CMV prophylaxis in the D+/R- renal transplant population.

1.a.2. Liver Transplant RecipientsValganciclovir is not approved as a drug for prophylaxis in liver transplant recipients in the United States because there is an increased risk of tissue-invasive CMV disease among patients who receive valganciclovir compared with among those who receive oral ganciclovir prophylaxis.14 Although the US Food and Drug Administration (FDA) has not approved valganciclovir prophylaxis for liver transplantation, most transplant centers in the United States continue to administer this drug as prophylaxis after liver transplantation.15,16 Valganciclovir has also been approved in other countries as prophylaxis for liver transplant recipients.

One recent study retrospectively evaluated 179 adult high-risk CMV D+/R- liver transplant recipients who received intravenous ganciclovir (5 mg/kg daily) for 14 days or until hospital discharge followed by either 3 months of oral ganciclovir (1 g three times daily) or 3 months of valganciclovir (900 mg daily).16 The CMV R+ patients did not receive intravenous ganciclovir but were given prophylaxis with oral ganciclovir or oral valganciclovir immediately after transplantation. The incidence of CMV disease was 4.6% in the oral ganciclovir group and 7% in the valganciclovir group (P=0.4), with a similar incidence of CMV infection in the D+/R- and R+ groups.16 These studies appear to support the current practice of administering valganciclovir prophylaxis to liver transplant patients.15,16 Indeed, current guidelines recommend valganciclovir as an option for antiviral prophylaxis in liver transplant recipients.1 Whether prophylaxis will need to be extended to 6 months for CMV D+/R- liver transplant recipients, based on the results of the

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Table 2

IMPACT trial in kidney transplant recipients, is a subject of intense debate. On the basis of the IMPACTtrial, some experts recommend administering 3-6 months of antiviral prophylaxis to high-risk CMV D+/R- liver transplant recipients.1

1.a.3. Lung Transplant RecipientsAmong solid organ transplant recipients, lung transplant recipients are considered at highest risk of CMV disease. Current guidelines recommend administering antiviral prophylaxis, most commonly with valganciclovir, to CMV D+/R- and CMV R+ lung transplant recipients, but the duration remains controversial. Prophylaxis was traditionally administered for at least 3 months, but the high rates of late- onset CMV disease led many centers to extend this prophylaxis to 6-12 months; other centers even extended the prophylaxis to CMV D+/R- lung recipients for a lifelong duration.

In recent years, several notable studies investigated antiviral prophylaxis for CMV disease in lung transplant recipients.17-20 In one center, the outcomes of valganciclovir prophylaxis for 12 months among CMV D+/R- lung recipients (N=59) and 6 months among CMV R+ recipients (N=61) were retrospectively reviewed.17 During the mean follow-up of 23 months after lung transplantation, 24/120 (20%) developed CMV viremia and 15/120 (12.5%) developed CMV disease. CMV disease occurred in 2% at 6 months, 11% at 12 months, and 15% at 18 months. The incidence of CMV disease was 22.5% in the group that stopped prophylaxis early compared with 6.2% in the group that completed therapy as prescribed (P=0.01). More CMV D+/R- patients (13/59 [22%]) developed CMV disease than CMV R+ patients (2/61 [3%]; P=0.003), suggesting that the risk of late-onset CMV disease remains high even among CMV D+/R- lung transplant recipients who have received 12 months of valganciclovir prophylaxis.17 Notably, no drug-resistant virus was observed.

At another center, the outcome of 109 CMV D+/R- lung transplant recipients who received a 900-mg daily dose of valganciclovir for a median of 8 months after lung transplantation was reviewed.18 Dose reductions were required in 17% of patients because of valganciclovir toxicity. During the 27-month follow-up period after lung transplantation, asymptomatic CMV viremia occurred in 41% of patients whereas CMV disease was observed in 27%. It is of interest that although most cases of CMV disease (18%) occurred after stopping prophylaxis, some cases (9%) occurred during prophylaxis. The breakthrough CMV disease cases occurred in patients who were receiving prophylaxis at a median of 6.7 months after transplantation, whereas late-onset CMV disease occurred in patients 2 months after stopping prophylaxis (median of 8.7 months after transplantation). In a multivariate analysis, advanced age (P=0.01) and a reduced dose of valganciclovir (P=0.0006) were independently associated with CMV disease. Ganciclovir-resistant CMV disease developed in 4% of patients, all of whom died.18

Thus far, the largest study of lung transplant recipients was a multicenter controlled trial of 136 lung transplant recipients who completed 3 months of prophylaxis with a 900-mg daily dose of valganciclovir and were then randomized to receive an additional 9 months of valganciclovir (extended-course; total of 12 months) or placebo (short-course; total of 3 months of prophylaxis).19 Prophylaxis was terminated early in 34% of the extended-course group and 31% of the short-course group. At 10 months’ follow-up from randomization (ie, at 13 months after lung transplantation), the rates of CMV syndrome or disease were 3.57% in the extended-course prophylaxis group and 32.1% in the short-course prophylaxis group (P<0.001). Any CMV infection occurred in 10.3% and 63.9% (P<0.001), respectively. These rates were not unexpected since the outcomes were analyzed only 1 month after the extended group had completed valganciclovir prophylaxis. Previous data18 suggest that late-onset CMV disease occurs at 1-3 months (median of 2 months) after stopping prophylaxis, and thus not all cases would have occurred at that time. In addition, there was no statistically significant difference in non-CMV infections or BPAR. One person in each group developed a CMV UL97 mutation known to confer ganciclovir resistance. As a secondary analysis, the investigators surveyed the patients at 6 months after study completion, and an additional 3% of the extended-course prophylaxis group and 2% of the short-course prophylaxis group developed CMV syndrome or disease.19 Based on other centers’ experience,17,18 particularly with regard to CMV D+/R- lung transplant recipients, the survey may have underestimated the true incidence of late-onset CMV viremia and disease among patients who received 12 months of valganciclovir prophylaxis.

A substudy of 38 CMV D+/R- and R+ lung transplant patients enrolled at a single center evaluated the long-term benefit and hematologic safety of extended valganciclovir prophylaxis.20 At 3.9 years of follow-up, the lifetime incidence of CMV was 12% in the extended-course prophylaxis group vs. 55% in the

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short-course prophylaxis group (P=0.002). There was no difference between the groups with regard to white blood cell count, absolute neutrophils, or platelets during follow-up.20 Based on these studies, extending prophylaxis to 6 months among CMV R+ lung transplant recipients and to at least 1 year among CMV D+/R- lung transplant recipients seems reasonable. Whether 12 months of prophylaxis is sufficient for high-risk CMV D+/R- lung recipients is still debatable. As mentioned previously, high rates of CMV disease are still being observed among CMV D+/R- lung transplant patients in other centers even though these patients are receiving 12 months of valganciclovir prophylaxis.17,18 Whether these differences relate to the underlying severity of immunosuppression is subject to further study.

1.a.4. CMV-Seropositive Transplant RecipientsCMV disease in CMV R+ kidney, pancreas, heart, and liver transplant recipients can be prevented either with antiviral prophylaxis or preemptive therapy. CMV R+ transplant recipients who also receive allografts from CMV-seropositive donors are at higher risk of CMV disease than those who receive allografts from CMV-seronegative donors. Although antiviral prophylaxis for 3 months appears to be sufficient for this patient group (who are at moderate risk of CMV disease after transplantation), some patients will still present with late-onset CMV disease.

A group of investigators from the University of Illinois compared no prophylaxis to a 450-mg daily dose of valganciclovir for 6 months in CMV R+ transplant patients and found a 6.7% and an 8.1% incidence of CMV infection, respectively. The median time to onset of CMV infection was delayed from 2 months among patients who did not receive any prophylaxis to 7.8 months among those who received 6 months of valganciclovir prophylaxis.5 Hence, this study indicated that antiviral prophylaxis delayed but did not significantly reduce the overall incidence of CMV infection in CMV R+ transplant patients.

An economic analysis compared CMV R+ patients who received prophylaxis with a 450-mg dose of valganciclovir with patients who were monitored and treated with a preemptive strategy.21 The investigators used a Markov transitional model using cost and QALYs from clinical data and published literature to determine the cost model. They found that within the first year after transplantation, CMV infection rates were 4.1% and 55.5% with antiviral prophylaxis and preemptive strategies, respectively. Although universal prophylaxis increased direct costs by $1,464, it saved $7,309 in indirect costs and resulted in a gain of 0.209 QALYs per patient over a 10-year period, resulting in a dominant cost-savings of $27,967 per patient with universal prophylaxis.21

1.a.5. Pediatric Transplant RecipientsThe efficacy of valganciclovir and ganciclovir were retrospectively compared in pediatric kidney and liver transplant patients. CMV R+ patients received 3 months of prophylaxis, whereas CMV D+/R- patients received 6 months of prophylaxis.15 After 2 weeks of intravenous ganciclovir therapy, patients received a 30 mg/kg/dose of oral ganciclovir (up to 1 g three times daily) or valganciclovir (daily dose in mg = 7 x body surface area x creatinine clearance by Schwartz equation) as compounded liquid. The incidence of symptomatic CMV infection or disease was 19.5% in the ganciclovir group and 13.7% in the valganciclovir group at 1 year posttransplantation (P=NS).15 Four children developed tissue-invasive CMV disease, including 2 liver transplant recipients, one kidney-alone transplant recipient, and one with a combined kidney-liver transplant.15

At a single center, valganciclovir prophylaxis (15 mg/kg per day; maximum 900 mg) was evaluated retrospectively for 24 weeks in pediatric kidney transplant recipients.22 At approximately 24 months’ follow-up, CMV viremia occurred in 27% of transplant recipients and CMV disease occurred in 4.5%. All cases of CMV disease occurred after prophylaxis ended, and all were in CMV D+/R- transplant patients. The use of rabbit antithymocyte globulin (vs. no antithymocyte globulin; P=0.04) and the receipt of an allograft from a CMV-positive donor (vs. CMV-negative donor; P=0.02) were associated with CMV viremia. Hematologic toxicity occurred in 24% of the pediatric kidney transplant patients.22

Data on pediatric heart transplant recipients (N=3,697) were obtained from the Scientific Registry of Transplant Recipients and reviewed to determine the effect of no prophylaxis, antivirals without CMV immunoglobulin (CMVIG), or CMVIG with or without antivirals.23 Administration of antivirals alone and CMVIG with or without antivirals was associated with significantly lower rates of graft loss and death relative to no prophylaxis at 7 years (P≤0.05). The optimal regimen, dose, and duration of antiviral and/or CMVIG therapy remain to be determined.23

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1.b. Preemptive TherapyPreemptive therapy is the second major strategy for preventing CMV disease after solid organ transplantation. This strategy consists of CMV surveillance to detect CMV replication in the blood, and, once detected, the use of antiviral therapy to treat the asymptomatic infection before it progresses to clinical disease. Surveillance for CMV is often started immediately after transplantation and conducted weekly thereafter for 12 weeks. Surveillance is usually conducted with a CMV polymerase chain reaction (PCR) assay or a pp65 antigenemia assay.

Antiviral therapy with valganciclovir (900 mg orally twice daily) or intravenous ganciclovir (5 mg/kg every 12 hours) is often administered, and the duration of therapy is guided by CMV surveillance. Investigators generally recommend continuing therapy until the results of two weekly consecutive CMV PCR or antigenemia assays are negative. This strategy is recommended by experts as an option for preventing CMV disease in CMV-seropositive kidney, pancreas, liver, and heart transplant recipients.1 Although several studies have demonstrated that this strategy is similarly effective in preventing CMV disease in transplant recipients, it is generally discouraged in high-risk CMV D+/R- kidney, heart, liver, pancreas, and small intestinal transplant recipients as well as CMV D+/R- and R+ lung transplant recipients because the rapid rates of CMV replication in these patients may lead to the development of CMV disease during the interval period of CMV surveillance.24 Comparative studies that assessed the efficacy of preemptive therapy compared with antiviral prophylaxis in solid organ transplant patients are limited to small studies, single- center trials, and meta-analyses. A large randomized controlled study to determine which of these two approaches is better for CMV prevention is warranted.

1.b.1. Kidney Transplant RecipientsSeveral small recent single-center studies have compared antiviral prophylaxis versus preemptive strategies in kidney transplant recipients. In one study, CMV monitoring and preemptive treatment with valganciclovir (900 mg twice daily for at least 14 days) was compared with 3 months of antiviral prophylaxis with valacyclovir (2 g four times daily) in 70 kidney transplant recipients.25 The 12-month incidence of CMV infection, as assessed by CMV DNAemia, was expectedly and significantly higher in the preemptive group than in the prophylaxis group (92% vs. 59%, respectively, P<0.001), but there was no statistically significant difference in the incidence of CMV disease (6% vs. 9%, P=0.567). As predicted, the onset of CMV DNAemia was delayed in the valacyclovir (187±110 days) group compared with the valganciclovir group (37±22 days) (P<0.001). There was a significantly higher rate of BPAR during the first 12 months in the preemptive group than in the prophylaxis group (36% vs. 15%, respectively, P=0.034). However, the long-term allograft and patient survival were similar between the groups.25

A second study enrolled CMV R+ kidney transplant recipients and randomized them to receive 100 days of prophylaxis with valganciclovir (900 mg daily) (N=99) or 28 days of preemptive therapy with valganciclovir (900 mg twice daily).26 At 24 months’ follow-up, there was no statistically significant difference in acute rejection, but the respective incidence of active CMV infection was expectedly higher in the preemptive strategy group than in the prophylaxis group (36% vs. 10.3%, respectively, P<0.0001), mostly in the D+/R+ kidney transplant patients (51.3% vs. 14.4%, P<0.0001). CMV disease occurred in 20.5% of the valganciclovir prophylaxis group (late-onset CMV disease) but in only 4.4% of the preemptive therapy group (P=0.0016). Graft loss occurred in 2.7% of the prophylaxis group and in 5.3% of the preemptive group (P=0.3782).26

The third study was a prospective randomized trial that compared 115 adult kidney transplant recipients who received prophylaxis with a 900-mg daily dose of valganciclovir for 100 days or preemptive therapy with a 900-mg twice daily dose of valganciclovir for 21 days.27 The primary outcome, which was a composite of freedom from acute rejection, graft loss, or death at 4 years, occurred in 83% of the prophylactic group and 81% of the preemptive group (P=0.754). Four patients in the prophylactic group and none of the patients in the preemptive group died with a functioning graft (8% vs. 0%, P=0.043).27 Finally, a recent meta-analysis of antiviral prophylaxis versus preemptive therapies demonstrated that prophylaxis was able to reduce CMV recurrence rates in adult kidney transplant recipients, with a risk ratio of 3.33 (95% CI, 1.43-7.73; P=0.005) relative to preemptive therapy.28

Collectively, these studies demonstrate that preemptive therapy is effective for the prevention of CMV disease in transplant recipients. Preemptive therapy has been demonstrated to be effective in CMV R+

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solid organ transplant recipients, and although this therapy may also be effective for high-risk CMV D+/R- non-lung solid organ transplant recipients in some centers, a large multicenter comparative clinical trial is needed to address this issue.

1.b.2. Preemptive Therapy to Prevent Late-Onset CMV DiseasePreemptive therapy has recently been suggested as a strategy to prevent the occurrence of late-onset CMV disease in high-risk CMV D+/R- solid organ transplant recipients who have completed antiviral prophylaxis. After patients have completed 100 or 200 days of valganciclovir prophylaxis, they should be monitored weekly for CMV replication and, on detection of CMV, antiviral therapy with either valganciclovir (900 mg twice daily) or intravenous ganciclovir (5 mg/kg twice daily) should be administered to prevent the progression of CMV to clinical disease.

This approach was examined in a cohort of 71 CMV D+/R- solid organ transplant recipients who, after completing 3-6 months of antiviral therapy, were monitored weekly by a CMV PCR assay for 8 weeks. The investigators reported that CMV disease occurred in 29 (40.8%) of 71 patients, with a significant proportion of disease (16 of 29) occurring beyond the 8-week surveillance period. Viremia occurred in 19 (26.8%) of 71 patients during the 8-week surveillance, and preemptive therapy was successfully used in only 3 (15.8%) of 19 viremic patients. Many patients had CMV disease (n=13) either at the first detection of viremia or before initiation of preemptive therapy because of rapid viral load doubling (median doubling time, 1.1 days).29 This rapid viral doubling time for CMV-naïve patients, together with the logistic difficulty of weekly blood surveillance during the later period after transplantation, limits the applicability of this hybrid prophylaxis-preemptive therapy approach.

1.c. Immunoglobulins for Prevention of CMV DiseaseImmunoglobulins were used for preventing CMV disease in transplant recipients before antivirals were available for prophylaxis, but the use of immunoglobulins has declined since oral antivirals became available for preventing CMV disease. Some data suggest that immunoglobulins have additional benefits in the prevention of CMV disease when they are combined with antivirals.30 In a meta-analysis, the use of immunoglobulins significantly reduced the risk of death from CMV disease (6 trials, 346 patients; risk ratio, 0.33; 95% CI, 0.14-0.80). Moreover, current guidelines acknowledge that immunoglobulins may be used in conjunction with antiviral drugs for preventing CMV in cardiothoracic organ transplant recipients.1

The benefits of CMVIG in terms of long-term allograft survival were examined in liver transplant recipients using data from the Scientific Registry of Transplant Recipients.31 This study compared liver transplant recipients who received CMVIG with antivirals (n=2350) or without antivirals (n=455), those who received antivirals without CMVIG (n = 32,939), and those who did not receive CMV prophylaxis (n=28,508). The endpoints included the incidence of acute rejection, graft loss, and death. In multivariate analysis, patients who received CMVIG with antivirals were at higher risk of acute rejection, but in the long-term they had a lower risk of graft loss and death.31

Collectively, data on the use of immunoglobulins for preventing CMV disease in solid organ transplant recipients remain debatable. It does appear, based on the limited number of studies, that immunoglobulins may be beneficial for preventing CMV disease in the long term. However, data from this meta-analysis should be interpreted with caution since no large prospective trial has ever been published that addressed this issue.

2. GANCICLOVIR RESISTANCE

Ganciclovir resistance is emerging as an important and difficult problem in transplant recipients. Ganciclovir resistance emerges when CMV develops a mutation in its UL97 gene, which then impairs its ability to produce the phosphokinase that will activate ganciclovir into its active form. Some cases of drug resistanceare caused by a mutation in the UL54 gene that encodes for CMV DNA polymerase, which is competitively inhibited by ganciclovir, foscarnet, and cidofovir to exert their antiviral effects. Most investigators believe that ganciclovir resistance is more common in highly immunosuppressed patients, who lack an immune response or have a markedly defective immune response to high levels of CMV replication. In this clinical setting, ganciclovir resistance is more common among CMV D+/R- and lung and pancreas transplant recipients. Most investigators also believe that ganciclovir resistance is more common when using a low-dose drug (such as oral ganciclovir or “mini-dose” valganciclovir) for a prolonged period.

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Because prolonged use of ganciclovir is believed to be a factor in the development of resistance, ganciclovir resistance is more common among patients who received antiviral prophylaxis than among those who received preemptive therapy. Most of the recent studies investigating antiviral prophylaxis regimens reported rates of ganciclovir resistance of 4% or less.2,17-20,32 In the IMPACT trial,2 3 cases of known mutations that conferred ganciclovir resistance were reported in each arm (short-term and long-term prophylaxis). In addition to well-defined resistance mutations, genotypic analysis may demonstrate other previously uncharacterized mutations and polymorphisms in the UL97 and UL54 genes. The clinical significance of these mutations is subject to further study. One of these studies evaluated 27 additional uncharacterized amino acid substitutions.33 Of these, 10 UL54 mutations in the 200-day group and 2 UL97 mutations and 14 UL54 mutations in the 100-day group were observed once each. In addition, UL54 E315D mutations were observed in 2 patients in the 200-day group and 1 patient in the 100-day group. Sixteen of these 27 mutations were tested for ganciclovir resistance, and none were associated with reduced ganciclovir susceptibility on phenotypic analysis.33

Contrary to previous observations, emerging data suggest that even patients who receive preemptive therapy are not immune to the development of ganciclovir resistance. In one cohort of 1,244 kidney transplant recipients who were monitored weekly with a CMV PCR assay and treated preemptively with a 900-mg daily dose of valganciclovir, UL97 resistance gene mutations were detected in 27 patients (2.2% of the population), with the majority (26 patients) belonging to the high-risk CMV D+/R- cohort.34 These data contradict previous assumptions that ganciclovir resistance is uncommon in patients receiving preemptive therapy. Instead, this study suggests that administration of a 900-mg once-daily dose of valganciclovir is a risky approach to preemptive treatment and that full-treatment doses of valganciclovir (900 mg twice daily) should be used. In addition, intravenous ganciclovir therapy should be strongly considered as first-line treatment for patients with CMV disease, especially those with high levels of CMV replication.

Ganciclovir resistance was retrospectively assessed in a cohort of CMV D+/R- kidney transplant recipients who received a purely preemptive regimen and those who received a sequential antiviral prophylaxis- preemptive regimen. The purely preemptive regimen (preemptive group) consisted of valganciclovir (900 mg given twice daily for 14 days), which was administered on detection of CMV DNAemia using a CMV PCR assay (N=42). The sequential prophylaxis-preemptive regimen (prophylaxis group) consisted of 90 days of valganciclovir prophylaxis (900-mg daily dose) followed by preemptive treatment (valganciclovir 900 mg twice daily for 14 days) on detection of CMV DNAemia (N=29).35 During the first year after transplantation, CMV DNAemia was present in 52% of the prophylaxis group and 69% of the preemptive group (P=0.14). One patient in the prophylaxis group and three patients in the preemptive group developed isolates that were resistant to ganciclovir, although all four patients cleared their virus without switching from valganciclovir.35 These data suggest that ganciclovir resistance may even develop with shorter durations of antiviral exposure (with preemptive therapy), possibly because patients with high levels of CMV replication may have been inadequately suppressed with oral valganciclovir. Indeed, one study from Japan demonstrated that maximal antigenemia was higher in the preemptive group than in the prophylaxis group. In addition, the two patients in this study who developed ganciclovir resistance mutations had received preemptive therapy.32

Another retrospective analysis of CMV D+/R- kidney transplant recipients that compared 32 patients receiving valganciclovir prophylaxis (900 mg daily for 3 months) to 80 patients receiving preemptive therapy (either intravenous ganciclovir [5 mg/kg every 12 hours] or valganciclovir [900 mg twice daily] ) because of a positive CMV PCR assay demonstrated the risk of resistance with preemptive therapy.36 Although there was an increased rate of ganciclovir resistance in the antiviral prophylaxis group, there was also an increased rate of resistance in the preemptive group (Table 3).36 As with previously mentioned studies,32,35 treatment failure and peak viral loads were significantly higher in the preemptive group than in the prophylaxis group.36 In fact, peak viral load was independently associated with the development of ganciclovir resistance (Figure 3). These data illustrate the risk of an oral and potentially low-dose therapy in patients with high levels of virus replication. The 1-year estimated glomerular filtration rate was lower in patients who developed ganciclovir resistance than in those who did not (41±24 vs. 58±20 mL/min, P=0.02), and 3 patients lost their graft to ganciclovir resistance; however, there were no statistically significant differences between the 1-year patient and graft survival rates.36

Collectively, it appears that underdosing valganciclovir during periods of high-level viral replication may be associated with ganciclovir resistance. Thus, preemptive therapy with valganciclovir during periods of

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higher peak CMV viral loads should be reconsidered because underdosing valganciclovir may contribute tothe development of ganciclovir resistance.34,36 Such resistance was also observed in a cohort of 85 intestinal transplant recipients, including 16 (18.82%) patients who developed CMV viremia.37 All patients werereceiving a ganciclovir formulation or failed to attain viral suppression while receiving a ganciclovir formulation. Of the 16 patients, 4 developed genotypic resistance (25%) and one developed clinical resistance (6.25%), for a total of 31.25% in the CMV viremia/disease group. Among the 5 patients with resistance, all were D+/R-, 80% had tissue-invasive CMV disease, and mortality was 60%. Ganciclovir exposure may have contributed to the development of resistance because of absorption issues, but the dosage and formulations were not specified.37

As shown above, ganciclovir resistance has an important impact on treatment outcomes. The time to CMV eradication is clearly delayed in patients with resistant virus, and treatment may entail the use of highly toxic antiviral drugs such as foscarnet and cidofovir.34 In general, immunosuppression is reduced in an effort to allow the immune system to clear the virus. In fact, for low-level resistance mutations, treatment with immunosuppression reduction alone may eliminate the need to switch from taking the antiviral drugs ganciclovir or valganciclovir to foscarnet or cidofovir.35 However, in many cases, ganciclovir resistance is associated with and often heralded by antiviral treatment failure, defined as a positive CMV PCR assay 8 weeks after initiating CMV treatment.36 The resistance was associated with higher peak CMV viral loads and appeared to affect 1-year renal function.36 Mortality is increased and graft survival is often decreased in patients with ganciclovir resistance, as is illustrated by a study of lung transplant recipients; in this study, mortality was 100% in 4 patients who developed ganciclovir resistance.18

3. MONITORING AND TREATMENT

CMV disease is manifested by fever, myelosuppression, myalgias, arthralgias, and signs and symptoms of end-organ involvement including diarrhea and abdominal pain (for gastrointestinal disease), shortness of breath and cough (for CMV pneumonia), elevated serum creatinine levels (for CMV nephritis), elevated liver enzyme levels (for CMV hepatitis), changes in mental function (for CMV encephalitis), and blurring of vision (for CMV retinitis). In patients with these symptoms, the diagnosis of CMV disease is confirmed by the detection of CMV in blood or tissues using a CMV PCR assay, a pp65 antigenemia assay, a viral culture, or histopathologic examination. Treatment should be initiated as soon as the disease is clinically suspected. The drugs of choice for the initial treatment of CMV disease are intravenous ganciclovir (5 mg/kg every 12hours, adjusted based on renal function); for patients with mild-to-moderate CMV disease, oral valganciclovir (900 mg twice daily) may suffice as initial treatment.38

Patients who are treated for CMV disease should be monitored for clinical and virologic response. Virologic monitoring consists of weekly CMV PCR or pp65 antigenemia assays, which will demonstrate a decline in viral load over time. The duration of treatment is generally individualized based on disease severity, clinical response, and virologic clearance. Because clinical response generally occurs sooner than viral eradication,

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Figure 3Table 3

it is important to document viral clearance before stopping antiviral therapy.39 This paradigm, to treat until the result of a CMV PCR assay is negative, is an effort to reduce the risk of virologic and clinical disease recurrence.40

Monitoring patients for virologic response has generally prolonged the treatment of CMV disease in many cases, especially in centers that use ultrasensitive PCR assays for detection. In general, whole blood samples are more sensitive for CMV DNA detection than plasma samples.41 Hence, it often takes longer to clear CMV DNA in whole blood than in plasma samples. To determine whether this has an impact on the rate of CMV disease resolution and relapse, a group of investigators recently compared the risk of relapse in 219 solid organ transplant patients who were monitored using whole blood or plasma. By 21 days of treatment, CMV DNA was still detectable in 70% of patients monitored by whole blood PCR compared with 52% of patients monitored with plasma. The positive predictive value for virologic recurrence was similar between the more-sensitive whole blood sample and the less-sensitive plasma sample. Moreover, in the subset of patients with negative plasma samples but positive whole blood samples, the incidence of virologic recurrence was similar to that of patients with negative plasma and negative whole blood assays (23.1% vs. 23.6%).42 This finding suggests that patients who are being monitored with ultrasensitive PCR assays may be receiving antiviral treatment for longer than needed.

Because of the lack of standardization among various assays, it has been difficult to uniformly apply guidelines for monitoring CMV after transplantation across centers. This lack of standardization limited the generation of widely applicable viral thresholds for disease prognostication, risk stratification, disease monitoring, and assessing risk of relapse. Such lack of standardization is well illustrated in a study that compared viral load reporting across 33 laboratories; in this study, the value reported for one sample varied among assays by as much as 3-4 logs.43

Moreover, blood monitoring is of limited value in some cases of tissue-invasive CMV disease. For example, some cases of gastrointestinal CMV disease and CMV retinitis will manifest as compartmentalized tissue-invasive disease with a low or undetectable viral load. Hence, a negative CMV PCR assay for blood does not completely rule out CMV disease involvement of the gastrointestinal tract or retina.44 Blood monitoring may also be limited in tissue-invasive CMV disease because the treatment will often clear the virus in the blood faster than it is eliminated in the involved tissue. A recent study clearly illustrates this point. A study of CMV D+/R- kidney (50%), liver (38%), and heart (12%) transplant recipients examined the predictors of treatment outcome and relapse following treatment of biopsy-proven late-onset primary gastrointestinal CMV disease.45 Patients received induction therapy with intravenous ganciclovir followed by valganciclovir treatment. The median time to obtain a negative CMV PCR test result in blood was observed earlier (at 22.5 days), and a normal endoscopic finding was observed later (at 27 days). CMV relapse occurred in 27% of patients and was associated with extensive disease (P=0.03) but not with endoscopic findings at the end of therapy.

Other methods are being developed for monitoring treatment responses; these methods include immunologic assays such as the whole blood interferon-gamma test measuring human CMV peptide antigens, cell-mediated immunity testing, cytokine profiling, T cell dynamics, and double-stranded RNA (dsRNA) sensors.46-50 These tests may help determine whether the virus requires treatment, whether spontaneous clearance could be expected, or when reactivation should be considered. Further work is required before these methods are ready for routine clinical use.

4. IMPROVING OUTCOMES: THE INDIRECT EFFECTS

The diagnosis of CMV disease needs to be improved, and more-effective treatment strategies are needed to counteract not only the direct effects of CMV disease but also its indirect effects. The association between CMV disease and acute allograft rejection and allograft survival is well described in the literature.In a recent study of 1,427 kidney (N=661), liver (N=494), heart (N=89), or double (N=183) transplants, the 103 (7.2%) patients who developed CMV disease within 1 year of transplantation were more likely to have developed or experienced acute rejection (31% vs. 20%; P=0.017) or to have died than patients who did not develop CMV disease (18% vs. 7%; P<0.001).51 Although this association is not consistent in studies, transplant physicians acknowledge the negative or adverse effect of CMV disease on transplant outcomes.52 Indeed, another group of investigators examined a large cohort of kidney transplant recipients (N=594) and, based on the results of protocol biopsies, a higher number of episodes of

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acute rejection were recorded in patients with CMV infection than in patients without infection (P=0.04).53 Renal function was best in patients without acute rejection or CMV infection and worst in patients with CMV infection and acute rejection (P<0.012 at 1 year; P<0.001 at 2 years).53

In another kidney transplant biopsy study, CMV immediate-early and late proteins were identified in 93% of end-stage chronic allograft dysfunction biopsy specimens and 64% of the corresponding early biopsy specimens.54 Graft survival was reduced in patients with moderate or high CMV levels in the allograft soon after transplantation compared with in patients with no or low CMV levels in the graft.54 Likewise, detection of CMV in bronchoalveolar lavage specimens of lung transplant patients was associated with the development of bronchiolitis obliterans syndrome (P=0.02), even when considered as a time-dependent variable (P=0.003).55 CMV infection was also recently independently linked to the development of donor-specific antibodies (P=0.009) in kidney and kidney/pancreas recipients and graft loss and death (P=0.001) or death (P=0.003) in liver transplant recipients compared with transplant recipients without CMV disease.56,57 These observations argue for the optimal prevention, rapid diagnosis, and early treatment of CMV disease after solid organ transplantation. Research and development are underway to address this goal.

5. FUTURE DIRECTIONS

5.a. Novel Antiviral TherapeuticsSeveral novel antivirals are undergoing clinical development for the prevention and treatment of CMV disease, and research on these new antivirals is timely because of the emergence of ganciclovir resistance. One of the promising novel drugs is AIC246, also known as Letermovir, a novel 3,4 dihydroquinazolinyl-acetic acid analog in phase IIb development. This drug is still in early clinical development, but it has been used on a compassionate basis for treating a lung transplant recipient with CMV disease that was resistant to the approved drugs ganciclovir, foscarnet, and cidofovir. This lung transplant patient developed multidrug- resistant CMV disease involving the lung, gastrointestinal tract, and retina.58 The patient, whose condition had failed to improve while receiving ganciclovir, foscarnet, cidofovir, and other off-label drugs such as leflunomide and an artemisinin derivative, improved following treatment with the investigational agent AIC246 (Letermovir).58

CMX001, the lipid formulation of cidofovir, is also being developed as an oral therapy for CMV infection and other double-stranded DNA viral infections.59 Maribavir, an investigational benzimidazole drug that inhibits UL97, was a promising antiviral agent until it was found to be not superior to placebo in phase III clinical trials in allogeneic stem cell transplant and liver transplant recipients.60 Before the phase III results, maribavir was available on a compassionate basis for the treatment of drug-resistant CMV disease because it has a unique mechanism of action compared with that of ganciclovir, foscarnet, and cidofovir.61 Finally, cyclopropravir is being developed as anti-CMV drug with a mechanism of action that may be similar to that of ganciclovir, although it retains its activity against ganciclovir-resistant CMV strains.62

5.b. CMV VaccineDevelopment of a CMV vaccine is considered a top priority by the Institute of Medicine. Interest in a CMV vaccine declined after the attenuated Towne CMV vaccine failed to prevent CMV infection in transplant recipients.63 Because vaccine recipients were less likely to develop severe CMV disease after transplantation, it was believed that the vaccine attenuated the clinical impact of CMV disease in transplant recipients. More recently, there has been remarkable interest in novel formulations of a CMV vaccine. Several are in clinical development, and the CMV glycoprotein B (gB) vaccine with the MF59 adjuvant is farthest along. This vaccine was recently tested in a phase II randomized placebo-controlled trial.64 The CMV gB-MF59 vaccine, given in 3 doses (months 0, 1, and 6) before transplant, was well tolerated and elicited high levels of antibodies against gB in both CMV-seronegative and CMV-seropositive vaccine recipients. The vaccine was given before transplantation, and vaccinees who received kidney or liver transplants had a lower incidence and degree of viremia and less need for antiviral therapy than those who received placebo. Moreover, the investigators demonstrated that the titer of anti-gB antibodies correlated inversely to the duration of viremia. This vaccine shows promise and should now proceed into phase III clinical trials.

5.c. Immune Monitoring and Prognostic FactorsImmunologic monitoring, a promising area of clinical investigation for CMV disease prevention and treatment,65-69 includes T-cell subset monitoring,65 monitoring of cell-mediated immunity,66 methods for

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recharacterization of CMV serostatus using T-cell immunity in pediatric transplant candidates,67 gene polymorphism,68 and pretransplant myeloid dendritic cell deficiency characterization.69 In one prospectivestudy, CD8+ T-cell response to CMV was characterized at the onset of CMV viremia to determine whether it could predict the clinical course of infection. As measured by the whole blood interferon-gamma test measuring human CMV peptide antigens, the incidence of subsequent spontaneous viral clearance was higher in patients with positive cell-mediated immunity (92.3%) than in those without cell-mediated immunity (45.5%; P=0.004). The absolute level of interferon-γ production was higher in patients with spontaneous viral clearance versus progression at all time points tested. Hence, detecting the status of CMV-specific cell-mediated immunity shortly after the onset of CMV viremia may be useful for predicting progression versus spontaneous viral clearance, thereby helping guide the need for antiviral therapy and refining current preemptive strategies.70

5.d. Selective Immunosuppressive RegimensDevelopment of CMV disease is clearly correlated with the severity of immunosuppression. Indeed, the “net state of immunosuppression” is considered as one of the major drivers for opportunistic infections. Because of the emerging body of data suggesting that certain immunosuppressive drugs are less likely to be associated with the development of CMV disease, it is possible to select optimal drug regimens to minimize the development of negative consequences of CMV disease. Preliminary data indicate that certain immunosuppressive agents prevent or limit the risk of developing CMV disease. These agents are, for example, relative to comparators, belatacept (vs. calcineurin inhibitors),71 alemtuzumab (vs. antithymocyte globulin),72 mizoribine (vs. mycophenolate mofetil),73 everolimus (vs. mycophenolate mofetil),74 and basiliximab (vs. antithymocyte globulin).75 Whether these preliminary observations will translate in the clinical arena is yet to be determined.

6. SUMMARY

The foregoing discussion provided a comprehensive review of the recent developments for preventing CMV disease after transplantation. With regard to prevention, there are solid data to suggest that extended prophylaxis with valganciclovir will further reduce the risk of late-onset CMV disease in high-risk CMV D+/R- solid organ transplant recipients, and this is now the standard of care in many centers. However, the optimal approach for non-high-risk transplant recipients (R+) is still not clear regarding prevention strategy choice and therapy duration and dose. Although extending antiviral prophylaxis decreases the overall disease burden, it is also clear that it does not completely eliminate the risk of developing late-onset CMV infection. The optimal method of preventing late-onset CMV disease is therefore being debated, with some investigators proposing preemptive therapy.

The dosing recommendation per guidelines and per clinical practice varies with conflicting data regarding risks (resistance development) and benefits (reducing adverse effects and cost savings). Concerns about the cost of extending antiviral prophylaxis is alleviated by an economic analysis that demonstrated that a 200-day prophylaxis regimen with a 900-mg daily dose of valganciclovir was more beneficial for CMV D+/R- patients than a 100-day regimen with a 900-mg daily dose of valganciclovir.13

Ganciclovir resistance is an emerging problem, albeit still rare. Although this complication was generally associated with prolonged antiviral prophylaxis, there are emerging data about its occurrence during the use of preemptive therapy. The development of resistance appears to be related to peak CMV viral loads during preemptive strategies and subtherapeutic exposure to valganciclovir during viral replication,7,17,36,37 and thus it is imperative that high levels of viral replication be treated with a formulation that reliably achieves high systemic concentrations. Most CMV disease, even among those who have been extensively exposed to ganciclovir, is still treated with intravenous ganciclovir or oral valganciclovir. Resistant cases, which are often heralded by nonresponding (rising or nondeclining) viral load, should be guided by genotypic assays to detect UL97 and UL54 mutations. Foscarnet and cidofovir are alternative treatments. Reduction in immunosuppression is also emphasized as an essential component of therapy for the management of drug-susceptible and resistant CMV disease. Novel strategies for monitoring and treating CMV disease are in development, as are ways to predict posttransplantation infectious risk and to select optimal immunosuppression to limit infectious risk.

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REFERENCES 1. Kotton CN, Kumar D, Caliendo AM, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2010;89:779-795. (A) 2. Humar A, Lebranchu Y, Vincenti F, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant. 2010;10:1228–1237. (A) 3. Humar A, Limaye AP, Blumberg EA, et al. Extended valganciclovir prophylaxis in D+/R- kidney transplant recipients is associated with long-term reduction in cytomegalovirus disease: two-year results of the IMPACT study. Transplantation. 2010;90:1427-1431. (A) 4. Helanterä I, Kyllönen L, Lautenschlager I, Salmela K, Koskinen P. Primary CMV infections are common in kidney transplant recipients after 6 months valganciclovir prophylaxis. Am J Transplant. 2010;10:2026-2032. (B) 5. West-Thielke P, Schmiedeskamp M, Aggarwal N, Thielke J, Oberholzer J, Benedetti E. Incidence and onset of cytomegalovirus infection in kidney transplant recipients: 3 months compared to 6 months of prophylaxis. Am J Transplant. 2011;11(Suppl s2):480. Abstract #1547 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B) 6. Luan FL, Kommareddi M, Ojo AO. Impact of cytomegalovirus disease in D+/R- kidney transplant patients receiving 6 months low-dose valganciclovir prophylaxis. Am J Transplant. 2011;11:1936-1942. (B) 7. Gabardi S, Asipenko N, Fleming J, et al. Efficacy and safety of six months of low- vs. high-dose valganciclovir for cytomegalovirus disease prevention in high-risk renal transplant recipients. Am J Transplant. 2011;11(Suppl s2):79. Abstract #161 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B) 8. Kalil AC, Mindru C, Florescu DF. Effectiveness of valganciclovir 900 mg versus 450 mg for cytomegalovirus prophylaxis in transplantation: direct and indirect treatment comparison meta-analysis. Clin Infect Dis. 2011;52:313-321. (A) 9. Eid AJ, Arthurs SK, Deziel PJ, Wilhelm MP, Razonable RR. Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes. Clin Transplant. 2008;22:162-170. (B)10. Welker H, Farhan M, Humar A, Washington C. Ganciclovir pharmacokinetic parameters do not change when extending valganciclovir cytomegalovirus prophylaxis from 100 to 200 days. Transplantation. 2010;90:1414-1419. (B)11. Wiltshire H, Hirankarn S, Farrell C, et al. Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients. Clin Pharmacokinet. 2005;44:495-507. (B)12. Limaye A, Blumberg E, Mu Y, et al. Evaluation of the Modification of Diet in Renal Disease (MDRD) equation versus the Cockcroft-Gault (CG) equation as a measure of renal function for valganciclovir dose calculations. Am J Transplant. 2011;11(Suppl s2):482. Abstract #1553 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)13. Blumberg EA, Hauser IA, Stanisic S, et al. Prolonged prophylaxis with valganciclovir is cost effective in reducing posttransplant cytomegalovirus disease within the United States. Transplantation. 2010;90:1420-1426. (B)14. Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2004;4:611-620.(B)15. Lapidus-Krol E, Shapiro R, Amir J, et al. The efficacy and safety of valganciclovir vs. oral ganciclovir in the prevention of symptomatic CMV infection in children after solid organ transplantation. Pediatr Transplant. 2010;14:753-760. (B)16. Fayek SA, Mantipisitkul W, Rasetto F, Munivenkatappa R, Barth RN, Philosophe B. Valganciclovir is an effective prophylaxis for cytomegalovirus disease in liver transplant recipients. HPB (Oxford). 2010;12:657-663. (B)17. Hammond SP, Martin S, Robert K, et al. CMV disease after lung transplantation. Am J Transplant. 2011;11(Suppl s2):456. Abstract #1466 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)18. Mitsani D, Nguyen MH, Kwak EJ, et al. Cytomegalovirus disease among donor-positive/recipient-negative lung transplant recipients in the era of valganciclovir prophylaxis. J Heart Lung Transplant. 2010;29:1014-1020. (B)19. Palmer SM, Limaye AP, Banks M, et al. Extended valganciclovir prophylaxis to prevent cytomegalovirus after lung transplantation: a randomized, controlled trial. Ann Intern Med. 2010;152:761-769. (A)20. Finlen Copeland CA, Davis WA, Snyder LD, et al. Long-term efficacy and safety of 12 months of valganciclovir prophylaxis compared with 3 months after lung transplantation: a single-center, long-term follow-up analysis from a randomized, controlled cytomegalovirus prevention trial. J Heart Lung Transplant. 2011;30:990-996. (A)21. Luan FL, Kommareddi M, Ojo AO. Universal prophylaxis is cost effective in cytomegalovirus serology-positive kidney transplant patients. Transplantation. 2011;91:237-244. (B)22. Camacho-Gonzalez AF, Gutman J, Hymes LC, Leong T, Hilinski JA. 24 weeks of valganciclovir prophylaxis in children after renal transplantation: a 4-year experience. Transplantation. 2011;91:245-250. (B)23. Snydman DR, Kistler KD, Ulsh P, Morris J. Cytomegalovirus prevention and long-term recipient and graft survival in pediatric heart transplant recipients. Transplantation. 2010;90:1432-1438. (B)24. Emery VC, Cope AV, Bowen EF, Gore D, Griffiths PD. The dynamics of human cytomegalovirus replication in vivo. J Exp Med.1999;190:177-182. (B)25. Reischig T, Jindra P, Hes O, Svecová M, Klaboch J, Treska V. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am J Transplant. 2008;8:69-77 (B)26. Witzke O, for the VIPP Study Group. CMV valganciclovir prophylaxis versus preemptive therapy after renal transplantation: two year results of a randomized clinical trial. Am J Transplant. 2011;11(Suppl s2):210. Abstract #LB05 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)27. Spinner ML, Saab G, Casabar E, Bowman LJ, Storch GA, Brennan DC. Impact of prophylactic versus preemptive valganciclovir on long-term renal allograft outcomes. Transplantation. 2010;90:412-418. (B)28. Zhang LF, Wang YT, Tian JH, Yang KH, Wang JQ. Preemptive versus prophylactic protocol to prevent cytomegalovirus infection after renal transplantation: a meta-analysis and systematic review of randomized controlled trials. Transpl Infect Dis. 2011;13:622-632. (A)29. Lisboa LF, Preiksaitis JK, Humar A, Kumar D. Clinical utility of molecular surveillance for cytomegalovirus after antiviral prophylaxis in high-risk solid organ transplant recipients. Transplantation. 2011;92:1063-1068. (B)30. Hodson EM, Jones CA, Strippoli GF, Webster AC, Craig JC. Immunoglobulins, vaccines or interferon for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev. 2007;(2):CD005129. (A)31. Fisher RA, Kistler KD, Ulsh P, Bergman GE, Morris J. The association between cytomegalovirus immune globulin and long-term recipient and graft survival following liver transplantation. Transpl Infect Dis. 2011 Aug 31. doi: 10.1111/j.1399-3062.2011.00664.x. [Epub ahead of print]. (B)32. Miura M, Harada H, Hotta K, et al. Impact of preemptive treatment after 3 months of valganciclovir prophylaxis for kidney transplant donor seropositive and recipient seronegative cases. Am J Transplant. 2011;11(Suppl s2):458. Abstract #1474 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)33. Chou S, Marousek G, Wong V, et al. The IMPACT Study: phenotypic analysis of previously uncharacterized cytomegalovirus UL54 and UL97 amino acid substitutions detected in virus from patients receiving 200 or 100 days of valganciclovir (Valcyte®) prophylaxis. Abstract #O06.02 presented at: XXIII International Congress of The Transplantation Society; August 15-19, 2010; Vancouver, Canada. www.transplantation2010.org (B)34. Myhre HA, Haug Dorenberg D, Kristiansen KI, et al. Incidence and outcomes of ganciclovir-resistant cytomegalovirus infections in 1244 kidney transplant recipients. Transplantation. 2011;92:217-223. (B)35. van der Beek MT, Berger SP, Vossen AC, et al. Preemptive versus sequential prophylactic-preemptive treatment regimens for cytomegalovirus in renal transplantation: comparison of treatment failure and antiviral resistance. Transplantation. 2010;89:320-326. (B)36. Couzi L, Helou S, Bachelet T, et al. High incidence of anticytomegalovirus drug resistance among D+R- kidney transplant recipients receiving preemptive therapy. Am J Transplant. 2012;12:202-209. (B)

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37. Yimen M, Goldstein D, Timpone T, Javan C. Cytomegalovirus resistance in intestinal transplant recipients. Am J Transplant. 2011;11(Suppl s2):279. Abstract #832 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)38. Asberg A, Humar A, Rollag H, et al. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2007;7:2106-2113. (B)39. Sia IG, Wilson JA, Groettum CM, Espy MJ, Smith TF, Paya CV. Cytomegalovirus (CMV) DNA load predicts relapsing CMV infection after solid organ transplantation. J Infect Dis. 2000;181:717-720. (B)40. Humar A, Snydman D; AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 2009;9(Suppl 4):S78-S86. (A)41. Razonable RR, Brown RA, Wilson J, Groettum C, Kremers W, Espy M, Smith TF, Paya CV. The clinical use of various blood compartments for cytomegalovirus (CMV) DNA quantitation in transplant recipients with CMV disease. Transplantation. 2002;73:968-973. (B)42. Lisboa LF, Asberg A, Kumar D, Pang X, Hartmann A, Preiksaitis JK, Pescovitz MD, Rollag H, Jardine AG, Humar A. The clinical utility of whole blood versus plasma cytomegalovirus viral load assays for monitoring therapeutic response. Transplantation. 2011;91:231-236. (B)43. Pang XL, Fox JD, Fenton JM, Miller GG, Caliendo AM, Preiksaitis JK; American Society of Transplantation Infectious Diseases Community of Practice; Canadian Society of Transplantation. Interlaboratory comparison of cytomegalovirus viral load assays. Am J Transplant. 2009;9:258-268.44. Grim SA, Pereira E, Guzman G, Clark NM. CMV PCR as a diagnostic tool for CMV gastrointestinal disease after solid organ transplantation [letter]. Transplantation. 2010;90:799-801. (B)45. Eid AJ, Arthurs SK, Deziel PJ, Wilhelm MP, Razonable RR. Clinical predictors of relapse after treatment of primary gastrointestinal cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2010;10:157-161. (B)46. Giulieri S, Manuel O. QuantiFERON®-CMV assay for the assessment of cytomegalovirus cell-mediated immunity. Expert Rev Mol Diagn. 2011;11:17-25. (B)47. Lisboa LF, Humar A, Silva M Jr, Huang J, Wilson LE, Kumar D. Clinical utility of cytomegalovirus cell mediated immunity in transplant recipients with low level CMV viremia. Am J Transplant. 2011;11(Suppl s2):115. Abstract #283 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)48. Lisboa LF, Kumar D, Silva M, et al. A comprehensive analysis of cytokine profiles in patients with cytomegalovirus (CMV) reactivation. Am J Transplant. 2011;11(Suppl s2):455. Abstract #1463 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)49. Silva M Jr, Kumar D, Lisboa LF, et al. An analysis of regulatory T-cell (Treg) and Th17 cell responses in transplant patients with CMV reactivation. Am J Transplant. 2011;11(Suppl s2):115. Abstract #281 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)50. Heutinck KM, Kassies J, Claessen N, Florquin S, Hamann J, ten Berge IJM. Expression of dsRNA sensors in the renal transplant is increased during cytomegalovirus, Epstein-Barr virus and BK virus infection. Am J Transplant. 2011;11(Suppl s2):232. Abstract #670 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)51. Linares L, Sanclemente G, Cervera C, et al. Influence of cytomegalovirus disease in outcome of solid organ transplant patients. Transplant Proc. 2011;43:2145-2148. (B)52. Abou-Ayache R, Büchler M, Le Pogamp P, et al. The influence of cytomegalovirus infections on patient and renal graft outcome: a 3-year, multicenter, observational study (Post-ECTAZ Study).Transplant Proc. 2011;43:2630-2635. (B)53. Erdbruegger U, Scheffner I, Mengel M, et al. Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies. Nephrol Dial Transplant. 2012;27:435-443. (B)54. Dzabic M, Rahbar A, Yaiw KC, et al. Intragraft cytomegalovirus protein expression is associated with reduced renal allograft survival. Clin Infect Dis. 2011;53:969-976. (B)55. Paraskeva M, Bailey M, Levvey BJ, et al. Cytomegalovirus replication within the lung allograft is associated with bronchiolitis obliterans syndrome. Am J Transplant. 2011;11:2190-2196. (B)56. Patel SJ, Devos JM, Knight RJ, et al. Donor specific antibodies and CMV infection in kidney/kidney-pancreas recipients. Am J Transplant. 2011;11(Suppl s2):43. Abstract #49 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)57. Bosch W, Heckman MG, Diehl NN, Shalev JA, Pungpapong S, Hellinger WC. Association of cytomegalovirus infection and disease with death and graft loss after liver transplant in high-risk recipients. Am J Transplant. 2011;11:2181-2189. (B)58. Kaul DR, Stoelben S, Cober E, et al. First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246. Am J Transplant. 2011;11:1079-1084. (case report)59. Price NB, Prichard MN. Progress in the development of new therapies for herpesvirus infections. Curr Opin Virol. 2011;1:548-554. (B)60. Marty FM, Ljungman P, Papanicolaou GA, et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis. 2011;11:284-292. (A)61. Avery RK, Marty FM, Strasfeld L, et al. Oral maribavir for treatment of refractory or resistant cytomegalovirus infections in transplant recipients. Transpl Infect Dis. 2010;12:489-496. (B)62. James SH, Hartline CB, Harden EA, et al. Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase. Antimicrob Agents Chemother. 2011;55:4682-4691. 63. Plotkin SA, Smiley ML, Friedman HM, Starr SE, Fleisher GR, Wlodaver C, Dafoe DC, Friedman AD, Grossman RA, Barker CF. Towne-vaccine-induced prevention of cytomegalovirus disease after renal transplants. Lancet. 1984;1:528-530. (B)64. Griffiths PD. A randomized placebo controlled trial of a CMV vaccine. Am J Transplant. 2011;11(Suppl s2):78. Abstract #157 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (A)65. Eid AJ, Brown RA, Arthurs SK, et al. A prospective longitudinal analysis of cytomegalovirus (CMV)-specific CD4+ and CD8+ T cells in kidney allograft recipients at risk of CMV infection. Transpl Int. 2010;23:506-513. (B)66. De Paolis P, Favarò A, Piola A, et al. “Immuknow” to measurement of cell-mediated immunity in renal transplant recipients undergoing short-term evaluation. Transplant Proc. 2011;43:1013-1016. (B)67. Schmidt T, Ritter M, Dirks J, et al. Refined definition of CMV infection status by determination of CMV specific T-cell immunity in individuals with passive antibody titers. Am J Transplant. 2011;11(Suppl s2):493. Abstract #1588 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)68. Hoffmann TW, Halimi JM, Büchler M, et al. Association between a polymorphism in the human programmed death-1 (PD-1) gene and cytomegalovirus infection after kidney transplantation. J Med Genet. 2010;47:54-58. (B)69. Sun Q, Hall EC, Chen P, et al. Pre-transplant myeloid dendritic cell deficiency associated with CMV infection and death following kidney transplantation. Am J Transplant. 2011;11(Suppl s2):161. Abstract #437 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)70. Lisboa LF, Kumar D, Wilson LE, Humar A. Clinical utility of cytomegalovirus cell-mediated immunity in transplant recipients with cytomegalovirus viremia. Transplantation. 2012;93:195-200. (B)71. Xu H, Mehta AK, Mead S, et al. Belatacept, but not calcineurin inhibitors, preserve human CMV-specific memory cell responses. Am J Transplant. 2011;11(Suppl s2):44. Abstract #52 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)72. Costa G, Cruz R, Bond G, et al. rATG versus alemtuzumab single dose pretreatment for visceral allograft recipients. Am J Transplant. 2011; 11(Suppl s2):133. Abstract #341 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)73. Tsuchida M, Uchiyama K, Fujikawa K, Kanaoka Y, Yoshihiro T, Matsuyama H. A novel immunosuppressive protocol using mizoribine combined with mycophenolate mofetil in kidney transplantation. Am J Transplant. 2011;11(Suppl s2):321. Abstract #983.5 presented at: American Transplant Congress; April 30-May 4, 2011; Philadelphia, PA. (B)74. Brennan DC, Legendre C, Patel D, et al. Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: pooled analysis of three clinical trials. Am J Transplant. 2011;11:2453-2462. (B)75. Ulrich F, Niedzwiecki S, Pascher A, et al. Long-term outcome of ATG vs. Basiliximab induction. Eur J Clin Invest. 2011;41:971-978. (B)

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© Copyright 2012 American Academy of CME, Inc and Spire Learning. All rights reserved.

1

A Review of Recent Research Updates in CMV

Instructions for Evaluation and Posttest Learners must 1) review the CME/CE information, including the learning objectives and disclosure statements; 2) study the monograph; 3) Complete the posttest (with a passing score of 70% or better) and evaluation using one of the two options below:

1. Go online to http://tinyurl.com/TRANSPLANTAZ, click on “Assessment,” and register on the site (or log in if you previously registered on the site). Upon successfully completing the posttest and evaluation, your certificate will be made available immediately to print online.

2. Complete the paper-based posttest and evaluation included at the end of the monograph and fax it to 609-921-6428. Your certificate will be sent to you within 6-8 weeks after your materials are received.

PLEASE PRINT CLEARLY. Name: ______________________________________________________________________________________________________

Address: ____________________________________________________________________________________________________

City: ______________________________________________ State: ____________ ZIP: __________________________________

E-mail address (in case we need to contact you): ___________________________________________________________________

Reenter E-mail address: _______________________________________________________________________________________

Time spent in the activity/credits claimed (physicians will receive credit for only the actual amount of time spent in the activity):

1.25 hours 1.0 hour 0.75 hours 0.5 hours 0.25 hours

___________________________________________________________________________________________ /________________

Signature Month and day of your birth (MM/DD)

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1. Professional title (please check one): Transplant Physician Transplant Surgeon Nurse/Nurse Practitioner AND Certified Transplant Coordinator Nurse/Nurse Practitioner only Pharmacist/PharmD Physician Assistant AND Certified Transplant Coordinator Physician Assistant only Healthcare Administrator Scientist/Researcher Other

If you selected “other,” please specify. ____________________________________________________________________ Transplant Coordinators: please provide your ABTC certification number: ______________________________ 2. Area of practice (check all that apply):

Kidney transplantation Liver transplantation Heart transplantation Lung transplantation Pancreas transplantation Other

If you selected “other,” please specify: ____________________________________________________________________ 3. Approximately how many transplants are performed annually at your transplant center? _______________ 4. Do you wish to be notified of future CME/CE-certified activities? Yes No

POSTTEST ANSWER FORM Please refer to the posttest on pages 5-6 for questions. Indicate your answers below, selecting one answer choice per question. A score of ≥70% is required to receive credit.

Posttest Question Number

A B C D

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

3

EVALUATION

1. I certify that I have participated in this educational activity. Yes

2. Please rate your level of agreement with the following statements:

Strongly Agree

Agree Neutral Disagree Strongly Disagree

The information was timely/up-to-date.

The activity met my expectations.

The content covered was useful and relevant to my practice.

The activity was fair, balanced, and free of commercial bias.

The information learned during this activity will help improve my skills or judgment within the next 6 months.

If you “disagreed” or “strongly disagreed” with any of the above, please explain.

____________________________________________________________________________________________________________

____________________________________________________________________________________________________________

3. Upon completion of this activity, I am better able to:

Strongly Agree

Agree Neutral Disagree Strongly Disagree

• Assess the clinical implications of results from recently released studies investigating CMV prophylaxis, preemptive strategies, monitoring, treatment, and resistance management

• Apply new evidence-based findings related to CMV prophylaxis, preemptive strategies, monitoring, treatment, and resistance management to my practice

4. Please rate each of the following:

Excellent Above Average

Average Below Average

Poor

The instructional effectiveness and expertise of the faculty authors

Effectiveness of the monograph format as a learning tool

Overall rating of this activity

4

5. Will this activity help you improve your (check all that apply): Competence Performance Patient Outcomes

6. Please list at least one new concept you will take away from this activity.

____________________________________________________________________________________________________________

____________________________________________________________________________________________________________

7. Based on the educational content of the activity, what will you do differently in the care of your patients? (Check all that apply.)

Implement a change(s) in my practice Seek additional information Do nothing differently—current practice reflects activity recommendations Do nothing differently—the content was not convincing Do nothing differently—system barriers prevent me from changing my practice Not applicable. I have no patient contact.

8. If you anticipate changing your practice, please briefly describe what you intend to do differently. (If you do not intend to do anything differently, please indicate “NA.”)

____________________________________________________________________________________________________________

____________________________________________________________________________________________________________

9. What is your level of commitment to making the practice change(s) stated above? Very committed Committed Somewhat committed Not very committed Do not expect to change practice Not applicable. Do not see patients.

10. What barrier(s) outside of your control impact your ability to make the practice change(s) you indicated above? (Check all that apply.)

Institutional Insurance/financial Lack of practice guidelines Time Lack of patient compliance/adherence Adverse effects of treatment Patient lack of knowledge regarding disease/treatment Other

If you selected “other,” please specify.

____________________________________________________________________________________________________________

5

11. What information would you like to see in future activities that may help you address those barriers?

12. What, if any, recommendations can you make to improve this activity?

____________________________________________________________________________________________________________

13. What patient problems or challenges related to CMV do you feel you are not able to address appropriately or to your satisfaction?

____________________________________________________________________________________________________________

POSTTEST

Please mark the correct answer for each of the following questions on the Posttest Answer Form provided on page 2.

1. Which of the following statements is CORRECT regarding the results from an economic analysis of the clinical trial that compared 100 versus 200 days of valganciclovir prophylaxis in kidney transplant recipients?

A. Costs were lower for the 200-day group compared with the 100-day group B. Quality-adjusted life years (QALYs) were decreased for the 200-day group compared with

the 100-day group C. The 200-day prophylaxis strategy is considered more cost saving than the 100-day

prophylaxis strategy over 10 years D. The 100-day group reported greater losses in productivity compared with the 200-day

group

2. Based on the results of studies that investigated the use of “mini-dosing” (450 mg of valganciclovir per day) prophylaxis strategies, which of the following would you expect to occur in CMV D+/R- kidney transplant recipients receiving a 450-mg daily dose of valganciclovir compared with those receiving a 900-mg daily dose of valganciclovir?

A. A lower rate of leukopenia B. A higher incidence of CMV disease C. A higher rate of myelosuppression D. A higher rate of acute rejection

3. Based on the results of a study comparing prophylaxis and preemptive strategies in CMV R+

kidney transplant recipients, which of the following endpoints occurred at a higher rate in the prophylaxis group?

A. CMV infection B. CMV disease C. Acute rejection D. Graft loss

4. Based on the studies described in this monograph, how long would you recommend that a CMV

D+/R- lung transplant recipient receive prophylaxis? A. 3 months B. 8 months C. 10 months D. At least 12 months

6

5. Based on studies presented in this monograph that investigated CMV prevention strategies for CMV R+ transplant recipients, which of the following results is CORRECT?

A. The onset of CMV infection in recipients who received a prophylaxis regimen consisting of a 450-mg daily dose of valganciclovir for 6 months was delayed compared with the onset of CMV infection in recipients who did not receive any prophylaxis

B. The overall incidence of CMV infection in recipients who received a prophylaxis regimen consisting of a 450-mg daily dose of valganciclovir for 6 months was reduced compared with the overall incidence of CMV infection in recipients who did not receive any prophylaxis

C. CMV infection rates in transplant recipients who received a prophylaxis regimen consisting of a 450-mg daily dose of valganciclovir were similar to CMV infection rates in transplant recipients who received a preemptive antiviral therapy regimen

D. A preemptive antiviral therapy regimen was associated with greater cost savings than a prophylaxis regimen consisting of a 450-mg daily dose of valganciclovir

6. Based on the studies presented in this monograph that investigated methods for CMV monitoring,

which of the following results is CORRECT? A. Plasma samples are more sensitive for CMV DNA detection than whole blood samples B. Patients who are monitored using ultrasensitive polymerase chain reaction (PCR) assays

may receive antiviral therapy for shorter durations than necessary C. Blood monitoring may not adequately detect some cases of tissue-invasive CMV disease D. CMV treatment often eliminates the virus from the involved tissue before it is cleared from

the blood

7. Based on the results of the studies presented in this monograph, which of the following factors most contributes to the development of ganciclovir resistance in kidney transplant recipients receiving preemptive antiviral therapy?

A. Low-dose immunosuppressive regimen B. Longer duration of preemptive antiviral therapy C. High peak CMV viral loads D. Transplant recipient’s overall health

8. Based on the results of studies presented in this monograph, which preemptive therapy regimen

would you recommend to reduce the risk of ganciclovir resistance in a CMV D+/R- kidney transplant recipient?

A. Once-daily 450-mg dose of valganciclovir B. Twice-daily 450-mg dose of valganciclovir C. Once-daily 900-mg dose of valganciclovir D. Twice-daily 900-mg dose of valganciclovir

9. Based on the results of studies presented in this monograph, which of the following indirect effects

was found to be associated with CMV disease in kidney, heart, and liver transplant recipients? A. Low rate of donor-specific antibodies B. Higher rates of acute rejection C. Bronchiolitis obliterans syndrome D. Longer allograft survival

10. Based on the studies presented in this monograph, which of the following findings is CORRECT

regarding the CMV gB/MF59 vaccine? A. The vaccine elicited high levels of antibodies against gB in CMV-seronegative vaccine

recipients but not in CMV-seropositive vaccine recipients B. Kidney and liver transplant recipients who received the vaccine had a similar degree of

viremia compared with those who received placebo C. Kidney and liver transplant recipients who received the vaccine had a similar need for

antiviral therapy compared with those who received placebo D. The titer of anti-gB antibodies correlated inversely with the duration of viremia