The median time to the progression of retinitis was 2.1 months, and 62 out of 78 patients had retinitis progression. No significant difference in the time to progression of the retinitis was observed between patients with detectable versus those with undetectable CMV DNA at baseline; nor between those positive versus those negative for CMV antigenemia at baseline.
Among patients with initially detectable CMV DNA in peripheral blood, those who remained positive at the 1 month follow-up visit had a similar risk of mortality (RR = 1.12, P = 0.80) and retinitis progression (RR = 0.96, P = 0.94) as those who became negative. Among patients initially positive for antigenemia, those who remained positive at 1 month had a higher risk of mortality (RR = 2.17, P = 0.10) and retinitis progression (RR = 1.91, P = 0.18) than those who became negative, but the differences were not statistically significant (see Table 4).
Our findings demonstrate that the detection of CMV DNA in the peripheral blood of patients with AIDS and CMV retinitis was associated with an increased risk of subsequent mortality. This result is similar to that observed by Bowen and colleagues  in patients with AIDS and CMV retinitis, and to several observations in patients with advanced AIDS at risk of CMV disease [8–10]. Our study also demonstrated that the detection of CMV DNA in peripheral blood was more strongly associated with the risk of mortality than was a high HIV viral load in patients with AIDS and CMV disease, similar to observations in patients with advanced AIDS without CMV disease [9,10]. Therefore, it seems reasonable to conclude that the increased risk of mortality when CMV DNA is detectable by PCR is similar whether CMV retinitis has already occurred or not. The detection of CMV antigenemia at baseline was not significantly associated with mortality in our study, a finding that differs from observations in patients with advanced AIDS but no CMV disease [14,17]. Because PCR for CMV DNA is technically more straightforward than the detection of CMV antigenemia , PCR may be the preferred method for studies of CMV viremia.
In our study, the time to progression of retinitis was not significantly different between patients with detectable and those with non-detectable CMV DNA in peripheral blood at baseline, as in the study by Bowen et al. . Nor were there differences in the risk of progression for patients with versus those without detectable CMV antigenemia at baseline. These observations support the theory that most retinitis progressions occur as a result of limited drug delivery to the retina after restoration of the blood–retinal barrier, rather than from the re-seeding of the retina with new virus from the blood. This conclusion is consistent with clinical intuition, in that most progressions involve the movement of existing borders of CMV lesions, rather than the development of new lesions. Systemically administered anti-CMV drugs are known to have limited penetration of the blood–retinal barrier, achieving a level approximately equal to the IC50 .
The strengths of our study include the prospective collection of specimens and clinical data, masked photographic evaluation of retinitis progression, long-term follow-up for mortality, relatively long follow-up of peripheral blood CMV-DNA results compared with previous studies, the relatively large study size compared with other studies evaluating CMV viremia in patients with AIDS and known CMV disease, and the simultaneous evaluation of CMV DNA, CMV antigenemia and HIV RNA in this patient group. In addition, our 15 center study may have provided a study population more representative of the general population than single center studies, improving generalizability. Limitations include the substantial losses to follow-up by the 6 month observation, mostly because of early mortality, non-uniform selection of anti-CMV treatment strategy, and limited sample size. Finally, this study was conducted largely in the era before HAART. HAART has resulted in improved immune function, and in many patients the improved control of retinitis, allowing selected patients to discontinue anti-CMV therapy [35–37]. How HAART will affect the relationship of CMV viral load to mortality among those with CMV retinitis remains to be determined.
The detection of CMV DNA in the peripheral blood of patients with known CMV retinitis and AIDS was associated with poorer survival, but was not predictive of retinitis relapse. PCR testing for CMV DNA appears to have greater predictive value for mortality than testing for CMV antigenemia in this group of patients. Although the available evidence suggests that a survival benefit may be obtained when CMV viremia can be successfully cleared by anti-CMV therapy, our study raises the concern that the clearance of CMV viremia may be short-lived in a substantial number of patients, possibly because of viral resistance. MSL-109 adjuvant therapy had no effect on CMV viremia.
The authors would like to thank Roche Molecular Systems, Inc., Pleasanton, CA, for donation of the CMV Monitor Assays. They would also like to thank INCSTAR Corporation, Stillwater, MN, for donation of CMV-vue antigenemia assays.
Conflict of interest: Financial disclosure statements are on file at the SOCA Coordinating Center, Johns Hopkins University School of Hygiene and Public Health.
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The Monoclonal Antibody Cytomegalovirus Retinitis Trial participating clinical centers
Baylor College of Medicine, Cullen Eye Institute, Houston: Richard A. Lewis, MD, MS (Director); Louise M. Carr-Holden, CRA; Kay Doyle, RN; Victor Fainstein, MD; Neal Gardner, RPh; Ronald Gross, MD; Silvia Orengo-Nania, MD; Varsha Patel, RPh; Tobias C. Samo, MD; James W. Shigley, CRA; Laura Shawver, COT; Steven S. Spencer, COMT; Mary Weinert, MD.
Emory University Clinic, Atlanta: Daniel F. Martin, MD (Director); Deborah Gibbs, COMT; John Jernigan, MD.
Johns Hopkins University School of Medicine, Baltimore: J.P. Dunn, MD (Director); John Bartlett, MD; Rebecca Becker, PA-C; Douglas A. Jabs, MD, MBA; Daniel A. Johnson, MD; John H. Kempen, MD, PhD; Susan LaSalvia, RN; Jo Leslie, PA-C; Janine Maenza, MD; Tracy Miller, LPN, COT; Laura G. Neisser, COT; Richard D. Semba, MD; Pamela Tucker, MD.
Louisiana State University Medical Center, New Orleans: Bruce Barron, MD (Director); Christine Jarrott, RN; Gholam Peyman, MD; Dennis Swenie, MD.
Memorial Sloan-Kettering Cancer Center and New York Hospital – Cornell Medical Center, New York: Murk-Hein Heinemann, MD (Director); Roberta Janis, RN; Bruce Polsky, MD; Kent Sepkowitz, MD.
Mount Sinai School of Medicine, New York: Alan H. Friedman, MD (Director); Robin Ginsburg, MD; Colette Severin, MS; Steven Teich, MD; Fran Wallach, MD.
New Jersey Medical School, New Jersey: Ronald Rescigno, MD (Director); Rosa Paez-Boham; Eileen Buroff; Patricia Kloser, MD; Maxine Wanner.
New York University Medical Center, New York: Dorothy N. Friedberg, MD, PhD (Director); Adrienne Addessi, MA, RN; Abraham Chachoua, MD; Douglas Dieterich, MD; Jason Hill; Richard Hutt, RN; Aditya Kaul, MD; Jonathan Ligh, MD; Monica Lorenzo-Latkany, MD; Maria Pei; Therese Powers, MS.
Northwestern University, Chicago: David V. Weinberg, MD, (Director); Lee M. Jampol, MD; Alice T. Lyon, MD; Annmarie Muñana, RN; Robert Murphy, MD; Frank Palella, MD; Len Richine; Zuzanna Strugala, OMA; Gloria Valadez.
University of California at Los Angeles, Los Angeles: Gary N. Holland, MD (Director); Margrit E. Carlson, MD; Suzette A. Chafey, RN, NP; W. David Hardy, MD; Ann K. Johiro, RN, MN, FNP; Lesley J. MacArthur-Chang, MEd; Maureen A. Martin, RN, MN, FNP; Ardis A. Moe, MD; Catherine A. Strong, MT, ASCP; Adnan Tufail, MB, BS, FRCOphth; Prabha S. Ugalat, BS; James M. Weisz, MD.
University of California at San Diego, San Diego: William R. Freeman, MD (Director); J. Fernando Arevalo-Colina, MD; Tom Clark, CRA; Cheryl L. Jarman; Linda Meixner, RN; Tze Chiang Meng, MD; Stephen Spector, MD; Ibrahim Taskintuna, MD; Francesca J. Torriani, MD.
University of California at San Francisco, San Francisco: James O'Donnell, MD (Director); Pierre Alfred, MD; Fermin Ballesteros; David Clay; Rebecca Coleman, PharmD; Kathleen Gordon, MD; Deborah Gumbley; Jacqueline Hoffman; Alexander Irvine, MD; Mark Jacobson, MD; James Larson, COT; Leonardo Macalalag; Michael Narahara; Mary Payne, RN; Stuart Seiff, MD; Scarlette Wilson, MD; Harlan Woodring.
University of Miami School of Medicine, Miami: Janet Davis, MD (Director); Anita Blenke; Inez Madera, RN; Paul Mendez, MD; Timothy Murray, MD.
University of North Carolina, Chapel Hill: Charles van der Horst, MD (Director); Jan Kylstra, MD; David Wohl, MD; Kimberlee Ziman, BA.
University of South Florida, Tampa: Peter Reed Pavan, MD (co-Director); W. Sanderson Grizzard, MD (co-Director); Gary A. Bergen, MD; Steven M. Cohen, MD; Jayne Ann Craig, OT; Richard L. Dehler, MD; Elizabeth Elbert, MD; Roger W. Fox, MD; Mark E. Hammer, MD; Lizette S. Hernandez, MD; Stacey Herrera; Douglas Holt, MD; Stephen Kemp, MD; Julie A. Larkin, MD; Dennis K. Ledford, MD; Richard F. Lockey, MD; Matthew M. Menosky, MD; Sharon Millard, RN, COT; Jeffrey P. Nadler, MD; Robert P. Nelson, Jr., MD; Dorece Norris, MD; L. David Ormerod, MD; Scott E. Pautler, MD; Sarah Jessica Poblete, MD; Dena Rodriguez, COT; Kevin P. Rosenbach, MD; Daniel W. Seekins, MD; John R. Toney, MD.
Chairman's Office, Johns Hopkins University School of Medicine, Baltimore, MD: Douglas A. Jabs, MD, MBA (Study Chairman); Joan M. Dodge; Joan L. Klemstine; Tracey A. Schuerholtz; Maria Stevens.
Coordinating Center, Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD: Curtis L. Meinert, PhD (Director); Aynur Unalp-Arida, MD, PhD; Debra Amend-Libercci; Laura Coleson-Schreur, RN, MPH; Karen L. Collins; Betty J. Collison; Chris Dawson; John Dodge; Michele Donithan, MHS; Cathleen Ewing; Nancy Fink, MPH; Charlotte Gerczak, MLA; Judith Harle; Janet T. Holbrook, MS, MPH, PhD; Robert Huffman; Milana R. Isaacson, BS; Adele M. Kaplan Gilpin, PhD, JD; John H. Kempen, MD, PhD; Madelyn Lane; Charlene R. Levine, BS; Barbara Martin, PhD; Jill Meinert; Yuan-I Min, PhD, MHS, MPH; Deborah J. Nowakowski; Rosetta M. Jackson; Maria J. Oziemkowska, MS, MPH; Bonnie Piantadosi, MSW, MPH; Alfred Saah, MD, MPH; Michael Smith; James Tonascia, PhD; Mark L. Van Natta, MHS.
Fundus Photograph Reading Center, University of Wisconsin, Madison, WI: Matthew D. Davis, MD (Director); Jane Armstrong; Judith Brickbauer; Rosemary Brothers; Marika Chop; Larry Hubbard, MAT; Dolores Hurlburt; Linda Kastorff; Michael Neider; Jim Onofrey; Vicki Stoppenbach; Marilyn Vanderhoof-Young.
Central Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD: Thomas C. Quinn, MD; Denise McNairn, MS.
Central Laboratory, University of Minnesota, Minneapolis, MN: Alejo Erice, MD; Marlene A. Holm.
Central Repository, University of Texas Medical Branch, Galveston, TX: Richard B. Pollard, MD; Pat Turk; Jason Urtis.
Drug Distribution Center, McKesson Bioservices Corporation, Rockville, MD: Mark Walls; Robert Hughes.
National Eye Institute, Bethesda, MD: Natalie Kurinij, PhD; Richard L. Mowery, PhD.
National Institute of Allergy and Infectious Diseases, Bethesda, MD: Beverly Alston, MD, Mary Foulkes, PhD.
Protein Design Laboratories, Mountain View, CA: Paul I. Nadler, MD; Debra L. Wood, MD; Marge Bladet; Nancy Wu.
Officers of the Study: Douglas A. Jabs, MD, MBA (Chair); Matthew D. Davis, MD; Natalie Kurinij, PhD; Curtis L. Meinert, PhD; Richard L. Mowery, PhD; James Tonascia, PhD.
Steering Committee: Douglas A. Jabs, MD, MBA (Chair); Adrienne Addessi, MA, RN; Beverly Alston, PhD; Tom Clark, CRA; Matthew D. Davis, MD; Judith Feinberg, MD; William Freeman, MD; Janet Holbrook, MS, MPH, PhD; Gary N. Holland, MD; Larry Hubbard, MAT; Mark Jacobson, MD; Natalie Kurinij, PhD; Richard A. Lewis, MD, MS; Leslie McArthur-Chang, MEd; Curtis Meinert, PhD; Richard Mowery, PhD; Robert Murphy, MD; Bruce Polsky, MD; James Tonascia, PhD.
SOCA-ACTG Joint Executive Committee: Douglas A. Jabs, MD, MBA (Chair); Matthew D. Davis, MD; William R. Duncan, PhD; Judith Feinberg, MD; Harold Kessler, MD; Natalie Kurinij, PhD; A. Garey Lambert (deceased); Natalie Kurinij, PhD; Curtis L. Meinert, PhD; Richard L. Mowery, PhD; William Powderly, MD; Steve Schnittman, MD; Steven Spector, MD; James Tonascia, PhD.
Policy and Data Monitoring Board: Byron W. Brown, Jr., PhD (Chair); Brian Conway, MD; James Grizzle, PhD; Robert Nussenblatt, MD; John P. Phair, MD; Harmon Smith, PhD; Richard Whitley, MD.
Non-voting members: Beverly Alston, MD; Matthew D. Davis, MD; Mary Foulkes, PhD; Douglas A. Jabs, MD, MBA; Natalie Kurinij, PhD; Curtis L. Meinert, PhD; Richard L. Mowery, PhD; James Tonascia, PhD.
Community Advisory Board: Ben Cheng; Kevin Frost; A. Garey Lambert (deceased); Michael Marco.
Viral Outcomes Committee: Thomas C. Quinn, MD (Chair); Alejo Erice, MD; Adele M. Kaplan Gilpin, PhD, JD; Douglas A. Jabs, MD, MBA; Yuan-I Min, PhD, MHS, MPH; Richard B. Pollard, MD.