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Extended Valganciclovir Prophylaxis to Prevent Cytomegalovirus After Lung Transplantation: A Randomized, Controlled Trial

Scott M. Palmer, MD, MHS; Ajit P. Limaye, MD; Missy Banks, BS; Dianne Gallup, MS; Jeffrey Chapman, MD; E. Clinton Lawrence, MD; Jordan Dunitz, MD; Aaron Milstone, MD; John Reynolds, MD; Gordon L. Yung, MD; Kevin M. Chan, MD; Robert Aris, MD; Edward Garrity, MD; Vincent Valentine, MD; Jonathan McCall, BA; Shein-Chung Chow, PhD; Robert Duane Davis, MD; and Robin Avery, MD
[+] Article and Author Information

From Duke University Medical Center and Duke Clinical Research Institute, Durham, North Carolina; University of Washington Medical Center, Seattle, Washington; Cleveland Clinic and Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio; Emory University, Atlanta, Georgia; University of Minnesota, Minneapolis, Minnesota; Vanderbilt University Medical Center, Nashville, Tennessee; Respiratory and Critical Care Consultants, Indianapolis, Indiana; University of California, San Diego, San Diego, California; University of Michigan, Ann Arbor, Michigan; University of North Carolina Hospitals, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; University of Chicago Medical Center, Chicago, Illinois; and Texas Transplant Center and University of Texas Medical Branch, Galveston, Texas.


Note: Drs. Davis and Avery contributed equally to this work.

Acknowledgment: The authors thank Jonathon Cook and Anthony Doll from the Duke Clinical Research Institute for assistance with the graphic design of Appendix Figures 1 and 2, respectively. The authors also thank Martha Wilbur from Duke University Medical Center, Department of Medicine, Pulmonary Division, for assistance with manuscript preparation. For a list of the study committees and members, principal investigators, and study coordinators, see the Appendix.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-1859.

Reproducible Research Statement:Study protocol: Available from Dr. Palmer (e-mail, palme002@mc.duke.edu). Statistical code and data set: Not available.

Requests for Single Reprints: Scott M. Palmer, MD, MHS, Lung Transplant Program, Department of Medicine, Duke University Medical Center, Suite 2073, Medical Science Research Building II, 106 Research Drive, Durham, NC 27710; e-mail, palme002@mc.duke.edu.

Current Author Addresses: Dr. Palmer: Lung Transplant Program, Department of Medicine, Duke University Medical Center, Suite 2073, Medical Science Research Building II, 106 Research Drive, Durham, NC 27710.

Dr. Limaye: University of Washington, Box 357110, 1959 NE Pacific Street, Seattle, WA 98195.

Ms. Banks: Duke Clinical Research Institute, 2400 Pratt Street, DUMC Box 3850, Duke University Medical Center, Durham, NC 27710.

Ms. Gallup: DCRI Statistics, Duke Clinical Research Institute, 2400 Pratt Street, DUMC Box 3850, Duke University Medical Center, Durham, NC 27710.

Dr. Chapman: Cleveland Clinic Main Campus, Mail Code A90, 9500 Euclid Avenue, Cleveland, OH 44195.

Dr. Lawrence: Emory University Hospital, 1364 Clifton Road NE, Atlanta, GA 30322.

Dr. Dunitz: Pulmonary/Critical Care Medicine, MMC 276 Mayo, 8276, 420 Delaware Street, Minneapolis, MN 55455.

Dr. Milstone: Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232.

Dr. Reynolds: Respiratory and Critical Care Consultants, 1801 Senate Boulevard, Suite 230, Indianapolis, IN 46202.

Dr. Yung: University of California, San Diego, Medical Center, 200 West Arbor Drive, San Diego, CA 92103-8373.

Dr. Chan: A. Alfred Taubman Health Care Center, 1500 East Medical Center Drive, Floor 3, Reception C, Ann Arbor, MI 48109-5361.

Dr. Aris: 4131 Bioinformatics Building, University of Chapel Hill, 130 Mason Farm Road, Chapel Hill, NC 27599.

Dr. Garrity: University of Chicago Medical Center, Center for Advanced Medicine, 5758 South Maryland Avenue, Chicago, IL 60637.

Dr. Valentine: University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0516.

Mr. McCall: DCRI Communications, Duke Clinical Research Institute, Durham Centre, Suite 800, 300 West Morgan Street, Durham, NC 27701.

Dr. Chow: Department of Biostatistics and Bioinformatics, DUMC Box 2721, Duke University Medical Center, 2424 Erwin Road, Durham, NC 27710.

Dr. Davis: Department of Surgery, DUMC Box 3864, Duke University Medical Center, Durham, NC 27710.

Dr. Avery: Department of Infectious Disease, Cleveland Clinic Main Campus, Mail Code G21, 9500, Euclid Avenue, Cleveland, OH 44195.

Author Contributions: Conception and design: S.M. Palmer, A.P. Limaye, M. Banks, J. Dunitz, R.D. Davis, R. Avery.

Analysis and interpretation of the data: S.M. Palmer, D. Gallup, G.L. Yung, R. Aris, S.C. Chow, R.D. Davis, R. Avery.

Drafting of the article: S.M. Palmer, J. McCall, R.D. Davis, R. Avery.

Critical revision of the article for important intellectual content: S.M. Palmer, A.P. Limaye, M. Banks, A. Milstone, G.L. Yung, E. Garrity, V. Valentine, J. McCall, R.D. Davis, R. Avery.

Final approval of the article: S.M. Palmer, A.P. Limaye, J. Chapman, E.C. Lawrence, A. Milstone, G.L. Yung, K.M. Chan, R. Aris, E. Garrity, V. Valentine, J. McCall, R.D. Davis, R. Avery.

Provision of study materials or patients: J. Chapman, E.C. Lawrence, J. Dunitz, A. Milstone, J. Reynolds, G.L. Yung, R. Aris, E. Garrity, R.D. Davis, R. Avery.

Statistical expertise: D. Gallup, S.C. Chow.

Obtaining of funding: S.M. Palmer, R.D. Davis.

Collection and assembly of data: S.M. Palmer, A.P. Limaye, D. Gallup, E.C. Lawrence, J. Dunitz, G.L. Yung, K.M. Chan, R.D. Davis, R. Avery.


Ann Intern Med. 2010;152(12):761-769. doi:10.7326/0003-4819-152-12-201006150-00003
Text Size: A A A

Background: Cytomegalovirus (CMV) is the most prevalent opportunistic infection after lung transplantation. Current strategies do not prevent CMV in most at-risk patients.

Objective: To determine whether extending prophylaxis with oral valganciclovir from the standard 3 months to 12 months after lung transplantation is efficacious.

Design: Randomized, clinical trial. Patients were randomly assigned by a central automated system to treatment or placebo. Patients and investigators were blinded to treatment status. (ClinicalTrials.gov registration number: NCT00227370)

Setting: Multicenter trial involving 11 U.S. lung transplant centers.

Patients: 136 lung transplant recipients who completed 3 months of valganciclovir prophylaxis.

Intervention: 9 additional months of oral valganciclovir (n = 70) or placebo (n = 66).

Measurements: The primary end point was freedom from CMV disease (syndrome or tissue-invasive) on an intention-to-treat basis 300 days after randomization. Secondary end points were CMV disease severity, CMV infection, acute rejection, opportunistic infections, ganciclovir resistance, and safety.

Results: CMV disease occurred in 32% of the short-course group versus 4% of the extended-course group (P < 0.001). Significant reductions were observed with CMV infection (64% vs. 10%; P < 0.001) and disease severity (110 000 vs. 3200 copies/mL, P = 0.009) with extended treatment. Rates of acute rejection, opportunistic infections, adverse events, CMV UL97 ganciclovir-resistance mutations, and laboratory abnormalities were similar between groups. During the 6 months after study completion, a low incidence of CMV disease was observed in both groups.

Limitation: Longer-term effects of extended prophylaxis were not assessed.

Conclusion: In adult lung transplant recipients who have received 3 months of valganciclovir, extending prophylaxis by an additional 9 months significantly reduces CMV infection, disease, and disease severity without increased ganciclovir resistance or toxicity. A beneficial effect with regard to prevention of CMV disease seems to extend at least through 18 months after transplantation.

Primary Funding Source: Roche Pharmaceuticals.

Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

CMV = cytomegalovirus.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 1.
Patient flow through valganciclovir study.

CMV = cytomegalovirus.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Primary study and secondary outcomes in randomized study cohort (intention-to-treat population).

CMV = cytomegalovirus. Top. Probability of CMV disease or syndrome from randomization to 10 months (300 days) after randomization. Bottom. Probability of any CMV infection from randomization to 10 months (300 days) after randomization.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.
Probability of tissue-invasive CMV disease to 10 months (300 days) after randomization.

CMV = cytomegalovirus.

Grahic Jump Location

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