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Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis

Kempen, John H; Min, Yuan-I; Freeman, William R; Holland, Gary N; Friedberg, Dorothy N; Dieterich, Douglas T; Jabs, Douglas A
OBJECTIVE: To evaluate the prevalence of and risk factors for immune recovery uveitis (IRU) in eyes of patients with AIDS and cytomegalovirus (CMV) retinitis. DESIGN: Enrollment data from a 19-clinical center cohort study. PARTICIPANTS: Three hundred seventy-four patients with AIDS and CMV retinitis affecting 539 eyes. METHODS: Patients with AIDS were enrolled at 19 United States AIDS ophthalmology clinics. Data were collected by interview, review of medical records, ophthalmic examination, and phlebotomy. MAIN OUTCOME MEASURE: Immune recovery uveitis. RESULTS: Thirty-six patients (9.6%) were diagnosed with IRU involving 50 eyes. The CD4+ T-cell count of 31 of these had risen by > or =50 cells per microliter above nadir to a level > or = 100 cells per microliter (immune recovery), making up 17.6% of the patients known to have immune recovery after diagnosis of CMV retinitis (95% confidence interval, 12.3%-24.1%). No patients with IRU were observed to have active retinitis or detectable CMV DNA in peripheral blood (P<0.001 and P<0.001 with respect to patients without IRU). Other factors associated with IRU were > or =25% retinal area (odds ratio [OR], 2.72; P = 0.014) or posterior pole involvement with CMV retinitis (odds ratio, 0.43; P = 0.039), treatment with intravitreous injection of cidofovir (OR, 10.6 with respect to eyes never exposed to intravitreous or IV cidofovir; P<0.001), and male gender (OR, 0.26; P = 0.012). More eyes with IRU had visual acuity (VA) of 20/50 or worse (38.0% vs. 26.3%, P = 0.077) relative to eyes without IRU, but the proportions with VA of 20/200 or worse were similar (14.0% vs. 13.8%, P = 0.96). Eyes with IRU more commonly had cystoid macular edema (CME) (45.5% vs. 3.7%, P<0.001) and epiretinal membrane (48.9% vs. 13.3%, P<0.001) than eyes without IRU. CONCLUSIONS: Among eyes of patients with immune recovery, the prevalence of IRU is substantial. Eyes with IRU have a high risk of additional morbidity over and above that seen with CMV retinitis, with several-fold higher risk of CME and epiretinal membrane. Large CMV lesions and use of intravitreous cidofovir are risk factors for IRU
PMID: 16581429
ISSN: 1549-4713
CID: 96106

Ocular complications

Chapter by: Friedberg DN; Lorenzo-Latkany M
in: Tuberculosis by Ron WN; Garay SM [Eds]
Philadelphia : Lippincott Williams & Wilkins, 2004
pp. 465-476
ISBN: 0781736781
CID: 3971

A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis

Lalezari, Jacob; Lindley, Janette; Walmsley, Sharon; Kuppermann, Baruch; Fisher, Martin; Friedberg, Dorothy; Lalonde, Richard; Matheron, Sophie; Nieto, Leopoldo; Torriani, Francesca J; Van Syoc, Rod; Sutton, Mary Ann; Buhles, William; Stempien, Mary Jean
Valganciclovir, an oral prodrug of the anti-cytomegalovirus (CMV) agent ganciclovir, was evaluated in a single-arm open-label safety study. AIDS patients (median CD4 lymphocyte count of 140 cells/microL) with treated CMV retinitis (N = 212) received 900-mg once-daily valganciclovir maintenance therapy with courses of 900-mg twice-daily valganciclovir induction therapy as needed to treat progression. After a median treatment duration of 372 days, the adverse event profile was similar to that reported for intravenous (IV) and oral ganciclovir. Adverse event rates of note were diarrhea (35%), nausea (23%), fever (18%), neutropenia (absolute neutrophil count <500 cells/microL) (10%), and anemia (hemoglobin <8.0 g/dL) (12%). Consistent with prior treatment studies of oral ganciclovir, IV catheter-related adverse events were uncommon (6%) and lower than previously reported for IV ganciclovir. The mortality rate was 0.072 deaths per patient-year. Progression of CMV retinitis occurred in 17% of patients during the study treatment period, usually in association with a low CD4 cell count. Other than a higher than expected frequency of oral candidiasis (17%), no clinical toxicities or laboratory abnormalities occurred during treatment with valganciclovir that have not been observed during treatment with ganciclovir.
PMID: 12138345
ISSN: 1525-4135
CID: 741572

High dose oral ganciclovir treatment for cytomegalovirus retinitis

Lalezari, Jacob P; Friedberg, Dorothy N; Bissett, Jack; Giordano, Michael F; Hardy, W David; Drew, W Lawrence; Hubbard, Larry D; Buhles, William C; Stempien, Mary Jean; Georgiou, Panos; Jung, Donald T; Robinson, Charles A
BACKGROUND: The oral formulation of ganciclovir is approved at a dose of 3.0 g/day for maintenance treatment of cytomegalovirus (CMV) retinitis following an initial induction course of intravenous (IV) anti-CMV therapy. Median time to progression of CMV retinitis is 12-20 days shorter with oral compared to IV ganciclovir maintenance, likely due to the limited oral bioavailability of ganciclovir. OBJECTIVES: We hypothesized that higher systemic drug exposures associated with increased doses of oral ganciclovir would be associated with increased efficacy. STUDY DESIGN: Maintenance treatment of CMV retinitis with higher than standard doses of oral ganciclovir (>3.0 g/day) was studied in 281 AIDS patients with previously treated, stable retinitis randomized to 3.0, 4.5 or 6.0 g/day oral, or 5 m/kg/day IV ganciclovir. Graders unaware of treatment assignments determined retinitis progression using fundus photographs. Vision, other ophthalmic measures and safety were assessed open-label. RESULTS: Median days to photographic progression were 41, 50, 57 and 70, respectively (P=0.052; 3.0 g vs. IV). Hazard ratios for progression relative to IV were 1.66, 1.28 and 1.19 (P=0.016 for 3.0 g). NONMEM-modeled estimates of average serum ganciclovir concentration area under the curve (AUC(0-24)) correlated best with time to progression (P=0.0019). Six grams per day oral ganciclovir was most similar in efficacy to IV, although broad confidence intervals prevented a conclusive comparison. Patients receiving oral ganciclovir had a lower frequency of sepsis and IV catheter events. CONCLUSIONS: This study suggests that the efficacy of ganciclovir for the maintenance treatment of CMV retinitis improves with increasing total drug exposure (measured as average serum concentration AUC(0-24)). All four regimens of ganciclovir were reasonably well tolerated, with safety profiles similar to what has been reported in prior work
PMID: 11744430
ISSN: 1386-6532
CID: 96107

Long-term follow-up of patients with AIDS treated with parenteral cidofovir for cytomegalovirus retinitis: the HPMPC Peripheral Cytomegalovirus Retinitis Trial - The Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group

Lewis, RA; Carr, LM; Doyle, K; Fainstein, V; Gross, R; Orengo-Nania, S; Samo, TC; Shigley, JW; Spencer, SS; Weinert, M; Dunn, JP; Bartlett, J; Becker, R; Feinberg, J; Jabs, DA; Johnson, DA; LaSalvia, S; Miller, T; Neisser, LG; Semba, RD; Tay-Kearney, ML; Tucker, P; Barron, B; Jarrott, C; Peyman, G; Swenie, D; Friedman, AH; Ginsburg, R; Sacks, H; Severin, C; Teich, S; Wallach, F; Rescigno, R; Cowan, J; Horan, C; Kloser, P; Wanner, M; Friedberg, DN; Addessi, A; Chachoua, A; Dieterich, D; Hill, J; Hutt, R; Ligh, J; Lorenzo-Latkany, M; Pei, M; Powers, T; Scoppe, C; Weinberg, DV; Jampol, LM; Lyon, AT; Munana, A; Murphy, R; Palella, F; Richine, L; Strugala, Z; Valadez, G; Holland, GN; Carlson, ME; Chafey, S; Hardy, WD; Johiro, AK; MacArthur-Chang, LJ; Martin, MA; Moe, AA; Strong, CA; Tufail, A; Ugalat, PS; Weisz, JM; Freeman, WR; Arevalo-Colina, JF; Clark, T; Jarman, CL; Meixner, L; Meng, TC; Spector, S; Taskintuna, I; Torriani, FJ; O'Donnell, J; Alfred, P; Ballesteros, F; Clay, D; Coleman, R; Gordon, K; Gumbley, D; Hoffman, J; Irvine, A; Jacobson, M; Larson, J; Macalalag, L; Narahara, M; Payne, M; Seiff, S; Wilson, S; Woodring, H; Davis, J; Mendez, P; Murray, T; Simmons, T; van der Horst, C; Kylstra, J; Wohl, D; Ziman, K; Pavan, PR; Bergen, GA; Cohen, SM; Craig, JA; Dehler, RL; Elbert, E; Fox, RW; Grizzard, WS; Hammer, ME; Hernandez, LS; Herrera, S; Holt, D; Kemp, S; Larkin, JA; Ledford, DK; Lockey, RF; Menosky, MM; Millard, S; Nadler, JP; Nelson, RP; Norris, D; Ormerod, LD; Pautler, SE; Poblete, SJ; Rodriguez, D; Rosenbach, KP; Seekins, DW; Toney, JR; Jabs, DA; Dodge, JM; Klemstine, JL; Schuerholtz, TA; Stevens, M; Meinert, CL; Amend-Libercci, D; Coleson, L; Collins, KL; Collison, BJ; Dawson, C; Dodge, J; Donithan, M; Ewing, C; Fink, N; Gerczak, C; Harle, J; Holbrook, JT; Huffman, R; Isaacson, MR; Gilpin, AMK; Lane, M; Levine, CR; Martin, B; Meinert, J; Nowakowski, DJ; Owens, RM; Piantadosi, B; Saah, A; Smith, M; Tonascia, J; Van Natta, ML; Davis, MD; Armstrong, J; Brickbauer, J; Brothers, R; Chop, M; Hubbard, L; Hurlburt, D; Kastorff, L; Magli, Y; Neider, M; Onofrey, J; Stoppenbach, V; Vanderhoof-Young, M; Walls, M; Hughes, R; Kurinij, N; Mowery, RL; Alston, B; Foulkes, M; Jabs, DA; Davis, MD; Kurinij, N; Meinert, CL; Mowery, RL; Jabs, DA; Addessi, A; Alston, B; Clark, T; Davis, MD; Feinberg, J; Freeman, W; Holbrook, J; Holland, GN; Hubbard, L; Jacobson, M; Kurinij, N; Lewis, RA; McArthur-Chang, L; Meinert, C; Mowery, R; Murphy, R; Polsky, B; Tonascia, J; Jabs, DA; Davis, MD; Duncan, WR; Feinberg, J; Kessler, H; Kurinij, N; Lambert, AG; Meinert, CL; Mowery, RL; Powderly, W; Schnittman, S; Spector, S; Tonascia, J; Brown, BW; Conway, B; Grizzle, J; Nussenblatt, R; Phair, JP; Smith, H; Whitley, R; Alston, B; Davis, MD; Foulkes, M; Jabs, DA; Kurinij, N; Meinert, CL; Mowery, RL; Tonascia, J; Jabs, DA; Freeman, WR; Jacobson, M; Murphy, R; Van Natta, ML; Meinert, CL; Cheng, B; Frost, K; Lambert, AG; Marco, M
Objective: To evaluate patients with cytomegalovirus (CMV) retinitis treated with intravenous cidofovir for long-term outcomes. Design: Patients with CMV retinitis enrolled in a randomized, controlled clinical trial of intravenous cidofovir as treatment for retinitis were followed for long-term outcomes, including 21 patients initially enrolled in the deferral group who received cidofovir therapy after progression of retinitis. Setting: Thirteen tertiary care clinics specializing in AIDS care and ophthalmology. Participants: Fifty-eight patients with AIDS and small peripheral CMV retinitis lesions. Interventions: Cidofovir 5 mg/kg once weekly for 2 weeks followed by low-dose maintenance cidofovir therapy (3 mg/kg) in 35 patients or high-dose maintenance (5 mg/kg) in 23 patients. Main outcome measures: Time to progression of retinitis, drug toxicities. Results: Median time to progression of retinitis was 2.5 months. Median time to discontinuation of cidofovir because of intolerance was 6.6 months, and did not differ significantly between the two maintenance doses. Median time to discontinuation of cidofovir for intolerance other than probenecid reaction was 16.3 months for patients treated with low-dose maintenance and 5.0 months for patients treated with high-dose maintenance (P = 0.021). Proteinuria of 2+ or more occurred at a rate of 1.22/person year. In patients with sufficient follow-up to determine resolution of proteinuria, 89.9% of episodes resolved, and the median time to resolution was 20 days. Rates of probenecid intolerance and of cidofovir-associated uveitis were 0.35/person-year, and 0.20/person-year, respectively
ISSN: 0269-9370
CID: 54539

Blurred vision during sexual arousal associated with narrow-angle glaucoma [Case Report]

Friedberg DN; Fox LE
PURPOSE: To describe three women with narrow-angle glaucoma who had transient blurred vision during sexual arousal. METHOD: Case reports. RESULTS: Three women, aged 37, 45, and 55 years, were seen with bilateral narrow-angle glaucoma and were treated with bilateral laser iridotomy. In each patient, additional surgery was required to control the glaucoma. After establishing a rapport with her physician, each patient described transient blurred vision, from a few minutes to several hours in duration, which began during sexual arousal. This symptom resolved after peripheral iridotomy and, in one patient, after laser iridoplasty. CONCLUSION: The association of transient blurred vision with sexual activity may delay presentation of patients with symptomatic narrow-angle glaucoma
PMID: 10577541
ISSN: 0002-9394
CID: 6245

Use of the ganciclovir implant for the treatment of cytomegalovirus retinitis in the era of potent antiretroviral therapy: recommendations of the International AIDS Society-USA panel [see comments] [Comment]

Martin DF; Dunn JP; Davis JL; Duker JS; Engstrom RE Jr; Friedberg DN; Jaffe GJ; Kuppermann BD; Polis MA; Whitley RJ; Wolitz RA; Benson CA
PURPOSE: To describe the risks, benefits, and recommended use of the ganciclovir implant for the treatment of human immunodeficiency virus-related cytomegalovirus (CMV) retinitis in the era of potent antiretroviral therapy. METHODS: A panel of physicians with expertise in the use of the ganciclovir implant and in the management of CMV retinitis was convened by the International AIDS Society-USA. The panel reviewed and discussed available data, and developed recommendations for the use of the ganciclovir implant, the surgical technique, and related management issues. Recommendations were rated according to the strength and quality of the supporting evidence. RESULTS: The effect of potent antiretroviral therapy on the immunologic status of patients with human immunodeficiency virus disease has changed the manifestation and course of CMV retinitis in many patients. The clinical management of CMV retinitis and the role of the ganciclovir implant are thus changing. Factors in the decision to choose the ganciclovir implant include the patient's potential for immunologic improvement, location and severity of CMV retinitis, and the risks and costs associated with implantation and concomitant oral ganciclovir therapy. CONCLUSIONS: The ganciclovir implant is safe and effective for the treatment of CMV retinitis. The indications for its use should be modified to account for increased patient survival and the potential for CMV retinitis to be controlled by effective antiretroviral therapy. Optimal use of the ganciclovir implant and discontinuation of therapy in selected patients with improvement in immunity may result in better long-term visual outcomes
PMID: 10088745
ISSN: 0002-9394
CID: 7402

Virus infections of the eye

Ritterband DC; Friedberg DN
In reviewing the clinical features, diagnostic evaluations and therapies of the most common ocular viral infections we attempt to whet your appetite for attacking the numerous challenges in diagnosis and treatment of viral eye disease. The herpes viruses, HSV, VZV and CMV are the cause of significant ocular morbidity. HSV most commonly affects the cornea producing keratitis that can be recurrent and may lead to corneal clouding and neovascularisation. Manifestations can be purely infectious or immunological and treatment options must be tailored to the underlying pathophysiology. Herpes zoster ophthalmicus, caused by VZV infection of the first branch of the trigeminal nerve, produces a characteristic rash and can progress to keratitis and uveitis. HSV and VZV can cause retinitis in both immunocompetent and immunocompromised individuals. There has been a significant increase in the incidence of CMV retinitis since the beginning of the AIDS epidemic. We review the numerous new treatments, diagnostic tests and treatment strategies which have been developed in response to this potentially blinding retinal infection. Adenovirus produces an epidemic conjunctivitis and epidemic keratoconjunctivitis which are severe and extremely contagious conjunctival infections. HIV, molluscum contagiosum, EBV and rubeola also cause ocular diseases which are described
PMID: 10398508
ISSN: 1052-9276
CID: 14729

Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA [Guideline]

Whitley RJ; Jacobson MA; Friedberg DN; Holland GN; Jabs DA; Dieterich DT; Hardy WD; Polis MA; Deutsch TA; Feinberg J; Spector SA; Walmsley S; Drew WL; Powderly WG; Griffiths PD; Benson CA; Kessler HA
OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. PROCESS: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included
PMID: 9588429
ISSN: 0003-9926
CID: 7850

Chronic multifocal retinal infiltrates in patients infected with human immunodeficiency virus [see comments] [Comment]

Levinson RD; Vann R; Davis JL; Friedberg DN; Tufail A; Terry BT; Lindley JI; Holland GN
PURPOSE: To describe the clinical features of a disorder characterized by chronic multifocal retinal infiltrates and uveitis in individuals with human immunodeficiency virus (HIV) disease. METHODS: We reviewed the medical records of HIV-infected patients with multifocal retinal infiltrates of unknown cause seen by investigators at four institutions. The following data were collected: demographic characteristics, presenting signs and symptoms, laboratory test results, and course of disease. RESULTS: We identified 26 HIV-infected patients (50 involved eyes) with this syndrome. Median CD4+ T-lymphocyte count at presentation was 272 per microl (range, 7 to 2,118 per microl). The most common presenting symptom was floaters. Median visual acuity of involved eyes at presentation was 20/20 (range, 20/15 to 20/100) and remained stable (median, 20/20; range, 20/15 to 20/70) after a median follow-up period of 9 months (range, 0 to 110 months). Typical retinal lesions were gray-white or yellow, irregular in shape, and less than 200 microm in greatest dimension. All were located in the midperiphery or anterior retina and enlarged slowly or remained static in size. Mild to moderate anterior chamber or vitreous humor inflammatory cells were present in 47 of 50 eyes (26 of 26 patients). Retinal lesions possibly responded to zidovudine but not to acyclovir or ganciclovir. Anterior chamber and vitreous humor inflammatory reactions responded to topical or periocular injections of corticosteroid. CONCLUSIONS: Uveitis with chronic multifocal retinal infiltrates is a distinct clinical entity of unknown cause that occurs in HIV-infected patients. Retinal lesions may respond to antiretroviral therapy. Visual prognosis is good
PMID: 9512148
ISSN: 0002-9394
CID: 7655