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Intraocular toxicity from didanosine was first reported in immunocompromised children who demonstrated peripheral chorioretinal atrophy after taking the drug.1 To date, there have been only 2 reports of didanosine-associated retinal toxicity in adults.2,3
We describe 3 additional cases of didanosine toxicity in adults infected with human immunodeficiency virus (HIV) who were receiving highly active antiretroviral therapy. Each patient had the typical presentation of midperipheral concentric chorioretinal atrophy. In addition, we highlight new findings using autofluorescence imaging, electroretinography, and spectral-domain optical coherence tomography and propose a pathogenetic mechanism for this toxicity.
A 35-year-old HIV-infected white man was examined in 1992 because of photopsia. His medications included zidovudine (600 mg/d) and didanosine (400 mg/d). His visual acuity was 20/15 OU. The results of an ocular examination were unremarkable.
In 2000, he was routinely reexamined. Zidovudine and didanosine had been discontinued after 6 years of use. His medications included nelfinavir mesylate (2.5 g/d), efavirenz (600 mg/d), and abacavir sulfate (600 mg/d). His visual acuity was 20/20 OU. An examination showed bilateral midperipheral chorioretinal atrophy extending anterior from the temporal arcades (Figure 1A and B).
Figure 1. Initial color fundus photographs, taken in 2000, showing atrophic patches concentrically distributed in the midperiphery of both eyes (A and B) of a 35-year-old white man infected with human immunodeficiency virus (case 1). Subsequent imaging with color fundus photographs in 2006 reveal progression and increasing confluency of atrophy with associated pigment migration (C and D). The most recent color fundus photographs in 2011 reveal continued progression of atrophic lesions (E and F).
In 2002, the patient was still asymptomatic, and his highly active antiretroviral therapy was modified to include zidovudine (150 mg/d) in fixed combination with lamivudine (300 mg/d; Combivir), fosamprenavir calcium (1.4 g/d), and lopinavir/ritonavir (800/200 mg/d) and was continued until the time of this report.
In 2005, he started to complain of bilateral visual field loss, which was documented by baseline formal visual field testing. Electroretinography revealed normal cone function but bilateral rod depression.
Serial fundus photographs dating from 2006 revealed progressive confluent bilateral chorioretinal atrophy with associated pigment migration (Figure 1C-F). His visual acuity was 20/25 OU. Autofluorescence imaging revealed hypoautofluorescence in the areas of atrophy, with intervening mottled-lacy hyperautofluorescence and hypoautofluorescence (Figure 2A-D). The results of spectral-domain optical coherence tomography through the midperipheral lesions showed severe chorioretinal atrophy, but the macula was within normal limits in each eye.
Figure 2. Autofluorescence (A and B) and Heidelberg optical coherence tomographic images (C [left panel] and D [left panel]) in 2011 revealing hypoautofluorescence in the areas of atrophy in both eyes of a 35-year-old white man infected with human immunodeficiency virus (case 1), with intervening lacy hyperautofluorescence and hypoautofluorescence in areas less involved and severe atrophy (C [right panel] and D [right panel]).
A 52-year-old HIV-infected man (with a CD4+ T-cell count of 242 cells/μL and an undetectable plasma HIV level) was referred for a 2-year history of progressive peripheral vision loss and nyctalopia in each eye. His ocular history was remarkable for optic neuritis in the left eye 8 years previously. He was taking efavirenz (600 mg/d), emtricitabine (200 mg/d), and tenofovir disoproxil fumarate (300 mg/d) and had used didanosine previously. There was a remote history of concurrent use of zidovudine.
His visual acuity was 20/20 OU, with a mild left afferent pupillary defect. The results of an examination of the anterior segment in each eye were unremarkable. A fundus examination revealed extensive midperipheral pigment mottling and chorioretinal atrophy in each eye (Figure 3A and B). Autofluorescence imaging revealed concentrically distributed, midperipheral mottled-lacy hyperautofluorescence and hypoautofluorescence (Figure 3C and D). Electroretinography revealed mild-to-moderate rod depression and borderline delay in cone implicit times in each eye. Humphrey visual field 30-2 revealed an inferior hemifield defect in the right eye and severe constriction in each eye. A systemic evaluation included a fluorescent treponemal antibody absorption test, a rapid plasma reagin test, a chest radiograph, and mitochondrial mutation analysis, the results of which were all negative.
Figure 3. Color fundus photographs of both eyes of a 52-year-old man infected with human immunodeficiency virus (case 2) revealing patches of atrophy in the midperiphery (A and B); midperipheral mottled-lacy hyperautofluorescence and hypoautofluorescence with concentric distribution on autofluorescence photographs of both eyes (C and D) of case 2.
A 54-year-old HIV-infected diabetic man (CD4+ T-cell count of 200 cells/μL and a plasma HIV level of 46 copies/mL) was referred for a several-year history of progressive peripheral vision loss and nyctalopia in each eye. His ocular history included bilateral cataract extraction and retinal detachment repair in the right eye. His medications included ritonavir (100 mg/d), maraviroc (600 mg/d), abacavir/lamivudine (600/300 mg/d), and darunavir (800 mg/d). There was a remote history of concurrent use of zidovudine. He had a remote history of dideoxycytidine use in 1995, which he stopped using in 1996 because of neuropathy, and didanosine use from 1996 to 1999.
His visual acuity was 20/80 OD and 20/70 OS. An examination of the anterior segment in each eye revealed pseudophakia. A fundus examination in each eye revealed symmetric peripheral pigmentary retinopathy (Figure 4A and B), a cryopexy scar superonasally, and a retinal macrocyst inferiorly in the right eye. Autofluorescence imaging revealed midperipheral mottled-lacy hyperautofluorescence and hypoautofluorescence in concentric distribution (Figure 4C and D). Electroretinography revealed a moderate symmetric panretinal depression throughout all rod- and cone-mediated responses and a delay in cone implicit times in each eye. Humphrey visual field 30-2 revealed 20° and 30° of constriction in the right and left eye, respectively.
Figure 4. Color fundus photographs of both eyes of a 54-year-old diabetic man infected with human immunodeficiency virus (case 3) revealing patches of atrophy in the midperiphery (A and B), an atrophic cryopexy scar in the superonasal periphery, and a retinal cyst inferiorly, as evidence of prior retinal detachment and its repair (A). Autofluorescence images reveal midperipheral mottled-lacy hyperautofluorescence and hypoautofluorescence with concentric distribution in both eyes (C and D). The superonasal periphery contains a hypoautofluorescent lesion with a hyperautofluorescent posterior border, as evidence of prior cryopexy therapy (C).
We present 3 cases of didanosine toxicity in HIV-infected adults, characterized by bilateral symmetric pigmentary retinopathy and concentric chorioretinal atrophy anterior to the arcades. Our patients had similar electroretinographic and autofluorescence findings, the latter showing peripheral hypoautofluorescence corresponding to patches of chorioretinal atrophy, with mottled-lacy hyperautofluorescence and hypoautofluorescence in areas of lesser involvement. Optical coherence tomography through the lesions showed severe chorioretinal atrophy. One of our patients was taking ritonavir but failed to demonstrate any of the characteristic macular findings associated with this HIV drug.4
The first reports of didanosine retinal toxicity involved children; findings were related to both peak and cumulative dosages of the drug,1 and the funduscopic presentation was consistent with our 3 cases. Electroretinographic, autofluorescence, and optical coherence tomographic findings in adults with presumed didanosine toxicity have not been previously described.
Didanosine (a purine analogue) is one of the earliest nucleoside reverse transcriptase inhibitors (NRTIs) approved for use, in 1991. Didanosine is used as part of the NRTI backbone of highly active antiretroviral therapy, which involves various groups of drugs, classified according to the mechanism of interference with the HIV life cycle. Current guidelines for highly active antiretroviral therapy recommend first-line treatment with 2 NRTIs, 1 protease inhibitor, and/or 1 non-NRTI.5
Didanosine has been shown to deplete wild-type mitochondrial DNA (mtDNA) and increase mutated mtDNA.6 Accumulating evidence has established NRTIs as a cause of mitochondrial toxicity due to depletion of DNA polymerase responsible for synthesis of mtDNA. There may be a more complex interplay between NRTIs and the natural systems of nucleotide phosphorylation, as well as direct inhibitory actions of these drugs on specific mitochondrial components.5
Didanosine toxicity has been associated with other mitochondrial syndromes, including chronic progressive external ophthalmoplegia,7 and can have a phenotypic funduscopic appearance similar to inherited mitochondrial degenerations such as Kearns-Sayre syndrome,maternally inherited diabetes and deafness, and the syndrome of mitochondrial encephalomyopathy with lactic acidosis, and strokelike episodes, although lesions of didanosine toxicity are located more peripherally. In addition, autofluorescence imaging of these mitochondrial disorders reveals a similar pattern of hypoautofluorescent concentric patches associated with mottled-lacy hyperautofluorescence and hypoautofluorescence.8 It is not surprising that a mitochondrial insult would manifest in the midperiphery, owing to the high metabolic demands of rods, which support photoreceptor outer segment disk turnover and the phototransduction cascade.
The development of didanosine toxicity appears to be rare, although the exact prevalence awaits prospective screening trials. The peripheral nature of this disorder may explain the delayed onset of symptoms. Autofluorescent findings suggest a progressive disorder that may be potentiated by the concurrent use of other NRTIs such as zidovudine, which had been or was being taken by all 3 of our patients. During in vitro testing on Kearns-Sayre syndrome fibroblasts, zidovudine depleted wild-type mtDNA and increased mutated mtDNA.6 Interestingly, all previously reported patients with didanosine toxicity had been treated with zidovudine. Follow-up autofluorescence imaging with a functional correlate may be helpful in monitoring patients for progression.
Correspondence: Dr Sarraf, Retinal Disorders and Ophthalmic Genetics Division, Jules Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095 (firstname.lastname@example.org).
Conflict of Interest Disclosures: None reported.
Funding/Support: This research was supported by a grant from the Cornell-Brewer Foundation to the Department of Ophthalmology, Rush University Medical Center, by the Karl Kirchgessner Foundation (Dr Sarraf), and by the Skirball Foundation, New York, New York (Dr Holland).
Gabrielian A, MacCumber MM, Kukuyev A, Mitsuyasu R, Holland GN, Sarraf D. Didanosine-Associated Retinal Toxicity in Adults Infected With Human Immunodeficiency Virus. JAMA Ophthalmol. 2013;131(2):255–259. doi:10.1001/jamaophthalmol.2013.579
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