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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Am J Ophthalmol. Author manuscript; available in PMC 2012 October 1.
Published in final edited form as:
PMCID: PMC3185165
NIHMSID: NIHMS291147

Evaluation of the United States Public Health Service guidelines for discontinuation of anti-CMV therapy after immune recovery in patients with CMV retinitis

Janet T. Holbrook, PhD, MPH,1 Ryan Colvin,1 Mark L. Van Natta, MHS,1 Jennifer E. Thorne, MD, PhD,1,2 Mark Bardsley, BSN,3 and Douglas A. Jabs, MD, MBA1,4,5, for the Studies of Ocular Complications of AIDS (SOCA) Research Group

Abstract

Purpose

To evaluate US Public Health Service (USPHS) guidelines for discontinuing anti-CMV therapy in patients with AIDS who have immune recovery and quiescent retinitis after initiating highly active anti-retroviral therapy (HAART).

Design

Cohort study of patients with CMV retinitis (Longitudinal Study of Ocular Complications of AIDS).

Methods

Participants had CMV retinitis and CD4+ T-cell counts of 50 cells/uL or fewer enrolled from 1998 to 2009 who demonstrated sustained immune recovery (two consecutive CD4+ T-cell counts of 100 cells/uL or more at least 6 months apart) and inactive retinitis. Participants were classified into 2 groups according to anti-CMV treatment after immune recover: (1) continued anti-CMV therapy and (2) discontinued therapy. We evaluated survival, visual acuity, and CMV retinitis activity; we employed propensity scores to adjust for confounding factors for these analyses.

Results

Of 152 participants reviewed, 71 demonstrated immune recovery; 37 of whom discontinued therapy and 34 who continued therapy. At immune recovery, participants continuing therapy tended to be older (44 vs 40 years, P=0.09), have bilateral retinitis (53% vs 32%, P=0.10), and have lower CD4+ T-cell counts (148 vs 207 cells/μL, P<0.001). There were no statistical differences in any of the clinical outcomes (death, retinitis progress, visual acuity or incidence of bilateral retinitis). Both groups lost visual acuity during follow-up, on average 1.2 letters per year (P<0.01).

Conclusion

Discontinuation of anti-CMV therapy after immune recovery did not increase the risk of poor outcomes. These results support the current guidelines for discontinuation of anti-CMV therapy after achievement of sustained immune recovery.

Keywords: CMV retinitis, immune recovery, maintenance therapy, USPHS guidelines

Introduction

Cytomegalovirus (CMV) retinitis is typically a late-stage opportunistic infection in patients with acquired immune deficiency syndrome (AIDS) and severe immunodeficiency, CD4+ T-cell counts fewer than 50 cells/uL. Before the introduction of highly active antiretroviral therapy (HAART) up to 30% of patients with AIDS developed cytomegalovirus (CMV) retinitis.1 Chronic maintenance therapy with an anti-CMV agent was required to prevent reactivation of the disease; time to retinitis progression after stopping therapy was typically 6 to 8 weeks.2,3 After the introduction of highly active anti-retroviral therapy (HAART), the incidence of CMV retinitis declined dramatically because of the preservation or restoration of immune function in many patients with AIDS associated with use of HAART.4 There have been several case-reports of patients with AIDS-related CMV retinitis who experience immune recovery, as evidenced by a sustained increase in CD4+ T cell counts to more than 100 cells/uL, reporting that they can discontinue maintenance therapy without reactivation of CMV retinitis.511 There have not been long-term studies comparing survival and vision loss in patients discontinuing treatment to those continuing treatment after immune recovery.

Based on the case reports of successful discontinuation of treatment without disease reactivation, the United States Public Health Service (USPHS) guidelines for secondary prophylaxis were revised in 1999 to suggest discontinuing anti-CMV therapy once patients with quiescent retinitis achieve sustained immune recovery.12 Continued close follow-up by an ophthalmologist is recommended since reactivation of retinitis and vision loss due CMV retinitis may occur among patients with CD4+ T-cell counts higher than 200 cells/uL, albeit at much reduced rates.10,1214 The purpose of this analysis was to evaluate and compare clinical outcomes (retinitis activity, visual acuity loss, and survival) between patients who continued on maintenance anti-CMV therapy after immune restoration compared to those who discontinued therapy according to the USPHS treatment guidelines. Participants with CMV retinitis enrolled and followed in the multicenter Longitudinal Study of Ocular Complications of AIDS (LSOCA) between 1998 and 2009 were evaluated.

Methods

LSOCA is a prospective, observational study designed to collect data on the incidence, prevalence, and complications due to AIDS-related ocular morbidities during the era of HAART.15,16 Recruitment began in 1998 at 19 clinical centers across the United States, most located in urban areas with large HIV-infected populations. The study is an open-cohort design, and recruitment is continuing to at least 2011. The protocol and consent statements were approved by Institutional Review Boards at all participating centers. Eligible patients were diagnosed with AIDS as defined by the 1993 Center for Disease Control diagnostic criteria for AIDS.17 Participants eligible for this analysis were enrolled from September 1998 to January 2009; the data base was frozen for this analysis as of 31 July 2009.

Participants with CMV retinitis were seen every 3 months for the first 10 years of the study (September 1998 – July 2008) after which they were seen every 6 months (August 2008 – July 2009). At each follow-up visit participants underwent an eye exam that included slit lamp exam and dilated indirect ophthalmoscopy, a medical history interview, and assessment of best-corrected visual acuity using logarithmic visual acuity charts according to a standard protocol.18 The location of the CMV retinitis lesion in each eye was categorized into three zones based on a standard classification system.19 Zone 1 is defined as the area within 1500 μm of the optic nerve or within 3000 μm of the center of the macula. Zone 2 extends from Zone 1 to the vortex veins and Zone 3 lies anterior to the vortex veins. Immune recovery uveitis was diagnosed clinically as the presence of intraocular inflammation in a patient who had undergone immune recovery. Laboratory tests obtained at each follow-up visit included hematology, lymphocyte subset analysis and HIV viral load determinations. Participants meeting the eligibility requirements described below were included in this analysis.

Eligible participants were those with a diagnosis of CMV retinitis at enrollment or during follow-up receiving anti-CMV treatment who had a CD4+ T-cell count of 50 cells/uL or fewer that were observed to have immune recovery during follow-up. Immune recovery was defined as having CD4+ T-cell counts of 100 cells/uL or greater at two or more consecutive visits at least 6 months apart. The date of immune recovery was set at the date of the second CD4+ T-cell count equal or greater than 100 cells/uL. We classified these participants according to the initial management strategy for maintenance therapy after immune recovery, i.e., was the USPHS recommendation initiated six months after immune recovery or not.11 Participants with CMV retinitis whose CD4+ T-cell counts were never observed to be fewer than 50 cells/uL were excluded since an approximate date of immune recovery could not be determined.

Characteristics at immune recovery were compared via Chi-square or Wilcoxon rank sum tests for categorical or continuous variable, respectively. We also evaluated mortality, retinitis progression, and changes in visual acuity, and compared these outcomes between the groups. Survival outcomes (mortality and retinitis progression) were evaluated with Kaplan-Meir curves and proportional hazards regression models with staggered-entry; the entry anchor time (time=0) was the date of immune recovery (the second consecutive CD4+ T-cell count greater than or equal to 100 cells/μL).20 Analyses needed to be adjusted for confounders since the allocation of patients to discontinue vs. continue therapy was not randomized and therefore prone to selection bias. Because the number of confounders was large relative to the number of observations, we chose to use propensity scores for covariate adjustment.21 Hazard ratios were adjusted for the following characteristics measured at the time of immune recovery: gender, CD4+ T-cell counts, age, bilateral disease status and time since CMV diagnosis; for eye-specific outcomes the percentage of retina involved with CMV retinitis was also included in the model and P-values were adjusted for patient-level clustering.22 For visual acuity, we defined time zero as the date of immune recovery and used general linear models with patient-level clustering to evaluate change in visual acuity over time.22

Results

We identified 152 participants with CMV retinitis at study enrollment or incident retinitis that occurred during follow-up that had CD4+ T-cell counts less than 50 cells/uL and were receiving anti-CMV therapy. Sixty-nine participants were diagnosed with CMV retinitis prior to study enrollment, 64 were diagnosed with CMV retinitis at enrollment and 19 were diagnosed during follow-up. Of these 152 participants, 71 (47%) had evidence of immune recovery during follow-up: 38 (55%) with CMV retinitis diagnosed prior to enrollment, 31 (48%) of those with a new diagnosis at enrollment, and 2 (11%) with incident disease during follow-up. Most of these 71 participants were observed to achieve immune recovery after January 2000 (Table 1). We followed these participants for a median time of 5 years (interquartile range: 3 to 7 years) after immune recovery.

Table 1
Characteristics of patients with CMV retinitis at immune recovery by treatment strategy (discontinuing vs continuing CMV Rx)

Thirty-seven of the eligible participants (52%) discontinued anti-CMV treatment within 6 months of achieving immune recovery, the remaining 34 patients continued on anti-CMV therapy for more than 6 months after immune recovery (Table 1); the median length of continuous therapy was 2.1 years (95% confidence interval 1.5, 2.7 years). Participants who continued anti-CMV therapy tended to be older and had lower CD4 counts at the time of immune recovery. Over 80% of participants in both groups were receiving HAART at the time of immune recovery and continued during follow-up (data not shown).

Participants who continued treatment tended to have a higher rate of bilateral disease, despite the fact that they tended to have a shorter duration from their diagnosis of CMV retinitis to immune recovery (Table 1). The median percentage of retinal area involved with retinitis was the same in both groups and the proportion with involvement of the posterior areas of the retina (zone 1 disease) was similar (Table 2). None of the eyes with CMV retinitis in either group had evidence of CMV lesion border activity at the time of immune recovery. The median visual acuity at immune recovery in eyes with CMV retinitis was less in the eyes of patient’s who discontinued treatment, but the difference was not statistically significant and both groups had similar levels of visual acuity impairment in involved eyes (Table 2).

Table 2
Characteristics of eyes with CMV retinitis at immune recovery by treatment strategy (discontinuing vs continuing CMV Rx)

There were no statistically significant differences in the development of bilateral retinitis, mortality, retinitis progression or visual acuity loss between the groups (Table 3, Figures 1: Kaplan-Meir curve for mortality). All cases of retinitis progression were associated with decline in CD4+ T-cell counts to fewer than 100 cells/μL, ranging from 3 to 66 cells/μL.

Figure 1
Kaplan-Meir Curve of time to death in years after immune recovery by CMV treatment status. Cont CMV Rx = continued CMV treatment is represented by the solid line; D/C CMV Rx = discontinued CMV treatment is represented by the dashed line.
Table 3
Clinical outcomes among immune recovered CMV retinitis patients by treatment strategy (discontinuing vs continuing CMV Rx)

Both groups experienced similar losses of visual acuity overtime at similar rates (P=0.94, Figure 2). The overall average rate of loss was 1.2 standard letter per year, which was significantly different from zero (p<0.01). The rates of visual loss to standard thresholds23, i.e., worse than 20/40 or 20/200 or worse, were high in both groups (Table 2) with nominally higher rates in the participants discontinuing anti-CMV treatment. However, that group tended to have a lower visual acuity at immune recovery, which may account for this trend.

Figure 2
Boxplots of visual acuity (standard letters) in eyes with CMV retinitis at 6 month intervals starting at immune recovery. Circle and triangle represent outliers for the discontinued and continued treatment groups, respectively. Cont CMV Rx = continued ...

The most common reason cited for a drop in visual acuity to worse than 20/40 was cataract (10 cases), uveitis with or without macular edema (4 cases, 2 of which were classified as immune recovery uveitis), CMV retinitis (4 cases), epiretinal membrane (3 cases), and optic nerve atrophy (1 case); in some cases more than 1 reason was cited and no reason was cited for 3 cases. Most of these eyes (11 of 14 in the discontinued group and 6 of 10 in the continued group) recovered vision to 20/40 or greater after the initial drop below 20/40 was noted. However, not all affected eyes returned to the level of vision measured at the time of immune recovery nor did all remain better than 20/40 after regaining visual acuity to that level.

We evaluated the influence of other factors on clinical outcomes. Women had a higher rate of death rate and higher rates of progression of CMV retinitis than men (data not shown). Higher viral loads at immune recovery were associated with higher risk of progression of CMV retinitis (data not shown). These variables were included as covariates in the adjusted analysis of risk (Table 3).

Discussion

Prior to introduction of HAART and other effective therapies for AIDS, HIV-related CMV retinitis was an end-stage opportunistic infection with a median life expectancy of less than a year after diagnosis.2 Patients with CMV retinitis now are likely to live much longer after diagnosis with substantially lower rates of retinitis progression generally with better clinical and visual acuity outcomes.4, 24 In 1999, the USPHS treatment guidelines for management of opportunistic disease were modified to recommend discontinuation of secondary prophylaxis for CMV retinitis in patient with sustained immune recovery after receiving HAART based on a few case-series that followed patients for retinitis activity.68 The recommendation in the most recent version of these guidelines is the same25, and also relies on case-series data focusing on CMV retinitis activity. We evaluated data from participants with CMV retinitis followed prospectively in LSOCA from 1998 to 2009. We identified patient who achieved immune recovery and compared clinical outcome for patients who discontinued therapy after immune recovery to those who continued therapy. Our evaluation is unique in that we included data on individuals who continued therapy after immune recovery for comparison, have a longer period of follow-up time (median follow-up of 5 years), and included outcomes not previously reported, i.e., mortality and visual acuity.

Our results show that after adjusting for potentially confounding factors, e.g., CD4+ T cell count, HIV load, bilateral lateral disease status, time since CMV retinitis diagnosis and age, participants who discontinue therapy did at least as well as participants who continued on therapy in terms of retinitis activity, visual acuity and survival. The characteristics of patients at immune recovery (Table 1) and the propensity score analysis indicate the factors that were most associated with the decision to continue treatment were lower CD4+ T-cell count, shorter time since CMV diagnosis, and female gender. The fact that CMV retinitis progression was uniformly associated with low CD4+ T-cell counts indicates that the primary reason for re-activation is immune compromise regardless of the treatment strategy. Furthermore, these results suggest that the phenomenon of immune system lacunae26, i.e., deficiencies in restoration of specific types of T-cells, after immune recovery is rare even in patients that have experienced severe immunodeficiency (all of our patients had a nadir CD4+of 50 cells/μL or fewer).

Visual acuity outcomes were similar in both groups; overall the average loss of visual acuity was 1.2 letters per year. The steady loss of acuity may indicate that despite control of CMV retinitis, these patients maybe at higher risk than other AIDS patients or the general public for significant vision loss over their lifetimes. Furthermore, patients with HIV and AIDS may develop visual function loss in the absence of CMV retinitis.27,28 There were relatively high rates of vision of declining to worse than 20/40 in eyes with retinitis, which is consistent with the steady decline in visual acuity observed.

Our results are strengthened by the fact they are from a multicenter prospective study with standard procedures for follow-up. The case-series addressing this question did not include patients whose treatment was not discontinued, nor did they evaluate longer-term clinical outcomes such as visual acuity or survival. Nonetheless, ours was a relatively small group of patients enrolled in an observational study and thus do not provide definitive evidence for the safety of discontinuing anti-CMV therapy in patients with AIDS and quiescent CMV retinitis after immune recovery. In fact, they illustrate well the difficulties of selection bias when using observational data to address the comparative effectiveness of different treatment strategies even with the use of statistical adjustment procedures to control for confounding by indication. Regardless, these results are the strongest evidence thus far in support of the USPHS guideline because they show that there is no evidence of shortened survival or worsened course of retinitis in patients discontinuing anti-CMV treatment after sustained immune recovery.

Acknowledgments

A. Financial support: Supported by cooperative agreements from the National Eye Institute, the National Institutes of Health, Bethesda, MD to the Mount Sinai School of Medicine, New York, NY (U10 EY08052); the Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (U10 EY08057); and the University of Wisconsin, Madison, Madison, WI (U10 EY08067).

Additional support provided by National Center for Research Resources through General Clinical Research Center grants:

5M01 RR 00350 (Baylor College of Medicine)

5M01 RR 05096 (LSU/Tulane/Charity Hospital)

5M01 RR00096 (New York University Medical Center, New York)

5M01 RR 00865 (University of California, Los Angeles)

5M01 RR00046 (University of North Carolina)

5M01 RR00043 (University of Southern California)

ULI RR024996 (Weill Medical College of Cornell University)

Support also provided through cooperative agreements:

U01 AI 27674 (Louisiana State University/Tulane)

U01 AI 27660 (University of California, Los Angeles)

U01 AI 27670 (University of California, San Diego)

U01 AI 27663 (University of California, San Francisco)

U01 AI25868 (University of North Carolina)

U01 AI32783 (University of Pennsylvania)

SOCA Research Group

Baylor College of Medicine, Cullen Eye Institute, Houston, TX: Richard Alan Lewis, MD, MS (Director); John Michael Bourg; Victor Fainstein, MD; Zbigniew Krason, CRA; Joseph F. Morales, CRA; Silvia Orengo-Nania, MD; Tobias C. Samo, MD; Steven Spencer, BA, COMT; Mitchell P. Weikert, MD. Former Members: Richard C. Allen, MD; Pamela Frady, COMT; Ronald Gross, MD; Allison Schmidt, CRA; Laura Shawver, COT/CCRP; James Shigley, CRA; Benita Slight, COT; Rachel Sotuyo, COT; Stephen Travers, CRA.

Emory University Eye Center, Atlanta, GA: Sunil K. Srivastava, MD (Director); Allison Gibbs, BS; Deborah Gibbs, COMT; Debora Jordan, CRA; Bob Myles, CRA; Janna Rutter, CRA. Former Members: Antonio Capone, Jr. MD; David Furukuwa, PA; Baker Hubbard, MD; Daniel F. Martin, MD.

Indiana University, Indianapolis, IN: Former Members: Mitchell Goldman, MD (Director); Janice Brown; Thomas Ciulla, MD; Jean Craft, RN, CS; Ronald Danis, MD; Paul Fry; Hua Gao, MD; Samir Gupta, MD; Janet Hernandez, RN; Debra Poe; Linda Pratt, RN; James D. Richardson, MD; Tim Steffens, CRA; L. Joseph Wheat, MD; Beth Zwickl, RN, CS, MSN.

Johns Hopkins University School of Medicine, Baltimore, MD: J.P. Dunn, MD (Director); Diane M. Brown, RN; Dennis Cain; David Emmert; Mark Herring; Adam Jacobowitz, MD; Henry A. Leder, MD; Alison G. Livingston, RN, BSN; Yavette Morton; Kisten D. Nolan, RN, BSN, MPH; Richard D. Semba, MD, MPH; Priscilla Soto; Jennifer E. Thorne, MD, PhD. Former Members: Patricia Barditch-Crovo, MD; Marie-Lyne Bélair, MD; Stephen G. Bolton, CRNP; Joseph B. Brodine; Lisa M. Brune, RN, BSN; Anat Galor, MD; Douglas A. Jabs, MD, MBA; Meera Kapoor; Sanjay R. Kedhar, MD; John H. Kempen, MD, PhD; Stephen J. Kim, MD; Armando L. Oliver, MD; George B. Peters, III, MD; Ricardo Stevenson, MD; Michelle Tarver-Carr, MD, PhD; Susan Wittenberg, MD; Michelle Yue Wang, MD.

Louisiana State University Health Sciences Center, New Orleans, LA: Donald Bergsma, MD (Director); Rebecca Clark, MD; Robin Cooper, COMT; Jasmine Elison, MD; Butler Fuller, MD; Christine Jarrott, RN, ACRN; Lynn Otillio, COT; Maria Reinoso, MD; Christine Romero, COT, ROUB. Former Members: Bruce Barron, MD; Robin Bye, RN; Mandi Conway, MD; Larry Dillon, COT/CRA; Audrey Lombard, RN; Gholman Peyman, MD.

New Jersey Medical School, Newark, NJ: Former Members: Ronald Rescigno, MD (Director); Neelakshi Bhagat, MD; Rosa Paez-Boham, COMT; Marta Paez-Quinde.

New York Hospital - Cornell Medical Center, New York, NY: Murk-Hein Heinemann, MD (Director); Susana Coleman; Sara Daniel; Roberta Janis, RN, BSN; Aziz Khanifer, MD; Andrzej Kozbial; Diane Iglesias Rivera, COA; Kent Sepkowitz, MD. Former Members: Kenneth Boyd; Robinson V.P. Chan, MD; Cynthia Chiu, MD; Charles Cole, MD; Charles Doering, MD; Jasmine Elison, MD; Sangwoo Lee, MD; Fang Lu; Joseph Murphy; Sophia Pachydaki, MD; Christina Peroni, MD; Firas M. Rahhal, MD; Ashok Reddy, MD; Scott Warden, MD.

New York University Medical Center, New York, NY: Dorothy N. Friedberg, MD, PhD (Director); Adrienne Addessi, MA, RN; Douglas Dieterich, MD; Monica Lorenzo-Latkany, MD; Maria Pei, COA. Former Member: Alex McMeeking, MD.

Northwestern University, Chicago, IL: Alice T. Lyon, MD (Director); Lori Ackatz, RN, MPH; Manjot Gill, MD; Lori Kaminski, RN, MS; Rukshana Mirza, MD; Robert Murphy, MD; Frank Palella, MD; Carmen Ramirez; Zuzanna Rozenbajgier; Dawn Ryan; Evica Simjanoski; Former Members: Alexander Habib; Jill Koecher; Jeevan Mathura, MD; Annmarie Muñana, RN; Jonathan Shankle; David V. Weinberg, MD; James Yuhr.

Rush University, Chicago, IL: Former Members: Mathew W. MacCumber, MD, PhD (Director); Bruce Gaynes, OD, PharmD; Christina Giannoulis; Pamela Hulvey; Harold Kessler, MD; Heena S. Khan; Andrea Kopp; Pauline Merrill, MD; Frank Morini; Nada Smith; Allen Tenorio, MD; Denise Voskuil-Marre; Kisung Woo.

University of California, Irvine: Former Members: Baruch D. Kuppermann, MD, PhD (Director); Bogdan Alexandiescu, MD; Donald N. Forthal, MD; Jeff Grijalva, COT; Faisal Jehan, MD; Karen Lopez; Rosie Magallon, BA; Nader Moinfar, MD; Bret Trump; Melody Vega, COA; Randy Williams.

University of California, Los Angeles: Gary N. Holland, MD (Director); Robert D. Almanzor, COA; Margrit E. Carlson, MD; Jose T. Castellanos, COT; Jeffrey A. Craddock, COT; Serina Gonzales; Ann K. Johiro, MN, RN, BC, FNP-C, AACRN, AAHIVS; Partho S. Kalyani, MD; Michael A. Kapamajian, MD; David L. LeBeck; Kristin M. Lipka; Susan S. Ransome, MD. Former Members: Suzette A. Chafey, RN, NP; Alexander C. Charonis, MD; Peter J. Kappel, MD; Ardis A. Moe, MD; Germán Piñón; Angela Sanderson; Kayur H. Shah, MD; Robert Stalling, COA; Dennis Thayer, CRA; Jean D. Vaudaux, MD.

University of California, San Diego: William R. Freeman, MD (Director); Denise Cochran; Igor Kozak, MD; Megan Loughran; Luzandra Magana; Victoria Morrison, MD; Vivian Nguyen ; Stephen Oster, MD. Former Members: Sunan Chaidhawanqual, MD; Lingyun Cheng, MD; Tom Clark; Mark Cleveland; Randall L. Gannon; Claudio Garcia, MD; Daniel Goldberg, MD; Joshua Hedaya, MD; Marietta Karavellas, MD; Tiara Kemper; Brian Kosobucki; Alona Mask; Nicole Reagan MD; Mi-Kyoung Song, MD; Francesca Torriani, MD; Dorothy Wong; Tekeena Young.

University of California, San Francisco: Jacque Duncan, MD (Director); Fermin Ballesteros, Jr.; Robert Bhisitkul, MD, PhD; Debra Brown; David Clay; Michael Deiner; Donald Eubank; Mark Jacobson, MD; Mary Lew, COT; Todd Margolis, MD, PhD. Former Members: Judith Aberg, MD; Jacqueline Hoffman; Alexander Irvine, MD; James Larson; Jody Lawrence, MD; Michael Narahara; Monique Trinidad.

University of North Carolina, Chapel Hill: Travis A. Meredith, MD (Director); Sandy Barnhart; Debra Cantrell; Seema Garg, MD, PhD; Elizabeth Hartnett, MD; Maurice B. Landers, MD; Sarah Moyer; David Wohl, MD;. Former Members: Stephanie Betran; Kelly DeBoer; David Eifrig, MD; John Foley, MD; Angela Jeffries; Jan Kylstra, MD; Barbara Longmire; Sharon Myers; Fatima N’Dure, COA; Kean T. Oh, MD; Jeremy Pantell; Susan Pedersen, RN; Cadmus Rich, MD; Cecilia A. Sotelo, RN; Charles van der Horst, MD; Samir Wadhvania.

University of Pennsylvania Medical Center, Philadelphia, PA: Charles W. Nichols, MD (Director); Mark Bardsley, BSN; Cheryl C. Devine; Jay Kostman, MD; Albert Maguire, MD; William Nyberg; Leslie Smith, RN. Former Members: Chris Helker, RN; RobRoy MacGregor, MD; Karen McGibney, RN; Keith Mickelberg, RN.

University of Southern California, Los Angeles, CA: Former Members: Jennifer I. Lim, MD (Director); Rizwan Bhatti, MD; John Canzano, MD; Thomas S. Chang, MD; Alexander Charonis, MD; Lawrence Chong, MD; Robert Equi, MD; Amani Fawzi, MD; Christina Flaxel, MD; Jesus Garcia; Todd Klesert, MD; Francoise Kramer, MD; Lori Levin, MPH; Tracy Nichols, COA, CRA; Christopher Pelzek, MD; Margaret Podilla, BS; Len Richine; Danny Romo, COA; Srinivas Sadda, MD; Richard Scartozzi, MD; Robert See, MD; Kevin Shiramizu, MD; Mark Thomas; A. Frances Walonker, CO, MPH; Alexander Walsh, MD; Ziquiang Wu, MD.

University of South Florida, Tampa, FL: Peter Reed Pavan, MD (Director); JoAnn Leto, COT; Brian Madow, MD; Richard Oehler, MD; Nandesh Patel, MD; Wyatt Saxon; Susan Sherouse, COT. Former Members: Andrew Burrows, MD; Steve Carlton; Burton Goldstein, MD; Sandra Gompf, MD; Bonnie Hernandez, COT; Mohan Iyer, MD; Patrick Kelty, MD; Amy Kramer, COT; Sharon Millard, RN, COT; Jeffrey Nadler, MD; Scott E. Paulter, MD; Jennifer Tordilla-Wadia, MD; Nancy Walker, COA.

University of Texas Medical Branch, Galveston, TX: Former Members: Garvin Davis, MD (Director); Robert Blem, MD; J. Mike Bourg, VA; John Horna, BS; Craig Kelso; Zbigniew Krason, BS; Helen K. Li, MD; Lan-Chi Nguyen, COMT; Rhonda Nolen, BS, CRC; Michelle Onarato, MD; David Paar, MD; Steven Rivas; Vicky Seitz, COT; Happy Spillar; Sami Uwaydat, MD.

Chairman’s Office, Mount Sinai School of Medicine, New York, New York: Douglas A. Jabs, MD, MBA (Study Chairman); Yasmin Hilal, MHS; Melissa Nieves, BA; Karen Pascual, BBA; Jill Slutsky, MPA; Maria Stevens, CM. Former member: Judith C. Southall.

Coordinating Center, The Johns Hopkins University Bloomberg School and Public Health: Curtis L. Meinert, PhD (Director); Alka Ahuja, MS; Debra A. Amend-Libercci; Karen L. Collins; Betty J. Collison; Ryan Colvin; John Dodge; Michele Donithan, MHS; Cathleen Ewing; Kevin Frick, PhD; Janet T. Holbrook, MS, MPH, PhD; Milana R. Isaacson, BS; Rosetta M. Jackson; Hope Livingston; Lee McCaffrey, MA; Milo Puhan, PhD; Girlie Reyes; Jacki Smith; Michael Smith; Elizabeth Sugar, PhD; Jennifer E. Thorne, MD, PhD; James A. Tonascia, PhD; Mark L. Van Natta, MHS; Annette Wagoner. Former members: Carley Benham; Ryan Colvin, Gregory Foster; Judith Harle; Adele M. Kaplan Gilpin, JD, PhD; John H. Kempen, MD, PhD; Barbara K. Martin, PhD; Nancy Min, MPH, PhD; Laurel Murrow, MS; Maria J. Oziemkowska, MS, MPH; Wai Ping Ng, BS; Pamela E. Scott, MA; Erica Smothers; Emily West; Claudine Woo, MPH; Albert Wu, MD, MPH; Alice Zong.

Fundus Photograph Reading Center, University of Wisconsin: Ronald Danis, MD (Director); Charles Chandler; Sapna Gangaputra, MD, MPH; Gregory Guilfoil; Larry Hubbard, MAT; Jeffrey Joyce; Thomas Pauli; Nancy Robinson; Dennis Thayer; Jeong Won Pak; Grace Zhang. Former members: Michael Altaweel, MD; Jane Armstrong; Matthew D. Davis, MD; Sheri Glaeser; Katrina Hughes; Dolores Hurlburt; Linda Kastorff; Michael Neider, BA; Therese Traut; Marilyn Vanderhoof-Young; Hugh Wabers;.

National Eye Institute, Bethesda, MD: Natalie Kurinij, PhD.

Officers of the Study: Douglas A. Jabs, MD, MBA (Chair); Ronald Danis, MD; Natalie Kurinij, PhD; Curtis L. Meinert, PhD; Jennifer E. Thorne, MD, PhD. Former Members: Matthew D. Davis, MD; Janet T. Holbrook, MS, MPH, PhD.

Steering Committee: Douglas A. Jabs, MD, MBA (Chair); Ronald Danis, MD; James P. Dunn, MD; Gary N. Holland, MD; Milana R. Isaccson, BS; Mark Jacobson, MD; Natalie Kurinij, PhD; Richard Lewis, MD, MS; Kisten D. Nolan, RN, BSN, MPH; Curtis L. Meinert, PhD; William Nyberg; Frank Palella, MD; Jennifer E. Thorne, MD, PhD. Former Members: Adrienne Addessi, MA, RN; Lisa Brune, RN, BSN; Rebecca Clark, MD; Tom Clark, CRA; Janet Davis, MD; Matthew D. Davis, MD; William R. Freeman, MD; Dorothy Friedberg, MD; James Gilman; Janet T. Holbrook, MS, MPH, PhD; John Horna; Larry Hubbard, MAT; Mark Jacobson, MD; Daniel F. Martin, MD; Travis A. Meredith, MD; Annmarie Muñana, RN; Robert Murphy, MD; P. Reed Pavan, MD; Steven Spencer, BA, COMT; Tim Steffens, CRA; Dennis Thayer; Charles van der Horst, MD; Fran Wallach.

Policy and Data Monitoring Board: John P. Phair, MD (Chair); Brian P. Conway, MD; Barry R. Davis, MD, PhD; Douglas A. Jabs, MD, MBA; Natalie Kurinij, PhD; Curtis L. Meinert, PhD; David Musch, PhD; Robert B. Nussenblatt, MD; Jennifer E. Thorne, MD, PhD; Richard Whitley, MD. Former Members: B. William Brown, Jr., PhD; Matthew D. Davis, MD; James Grizzle, PhD; Argye Hillis, PhD; Janet T. Holbrook, MS, MPH, PhD; Harmon Smith, PhD; James A. Tonascia, PhD.

Visual Function Quality Assurance Committee: Steven Spencer, BA, COMT (Chair); Robert D. Almanzor; Deborah Gibbs, COMT; Milana Isaacson, BS; Mary Lew, COT ;Richard Alan Lewis, MD, MS (Advisor);. Former Members: Ferman Ballesteros; Jeff Grijalva, COT; Karen Lopez; Laura G. Neisser, COT; Rosa Paez-Boham, COST.

Biography

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Janet Holbrook, PhD, MPH is an associate professor of epidemiology at the Johns Hopkins University Bloomberg School of Public Health in Baltimore, Maryland. She is member of the Center for Clinical Trials, which is a multidisciplinary group focused on research and scholarship in the areas of clinical trials evidence-base healthcare. She graduated from the Universities of Maryland and California and received her doctoral degree from The Johns Hopkins University.

Footnotes

B. Financial disclosures:

Dr. Holbrook has received grant support from the National Eye Institute, the National Heart, Lung and Blood Institute and the American Lung Association. Mr. Colvin and Mr. Van Natta have received grant support from the National Eye Institute, the National Heart Lung and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Disease.; Mr. Bardsley has received grant support from the National Eye Institute; Dr. Thorne has received grant support from the National Eye Institute, Research to Prevent Blindness; and Dr. Jabs has received grant support from the National Eye Institute and consulting fees from Roche Pharmaceuticals, GlaxoSmithKline, Alcon Laboratories, and Applied Genetic Technologies Corporation (all <$10,000)

C. Contributions of Authors: Design of study (JTH, MLV, DAJ); Conduct of study (JTH, MLV, MB, JET, DAJ), Analysis of data (JTH, RC, MLV), Interpretation of results (JTH, MLV, MB, JET, DAJ); writing and revision of paper (JTH, RC, MLV, MB, JET, DAJ)

D. Statement about conformity: The study was approved by the IRBs at all participating centers. The consent statements were HIPAA compliant. The responsible IRB is Johns Hopkins University Bloomberg School of Public Health Committee on Human Research

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