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Retinal toxicity with Ritonavir
Received: 2014-11-23
Accepted:
2015-07-27
DOI:10.18240/ijo.2016.04.29
Citation: Tu Y, Poblete RJ, Freilich BD, Zarbin MA,
Bhagat N. Retinal toxicity with Ritonavir. Int J Ophthalmol 2016;9(4):640-642
Dear sir,
Non-systemic, ocular
toxicity caused by medications used in highly active antiretroviral therapy
(HAART) for human immunodeficiency virus (HIV) infection is an uncommon adverse
event[1]. Roe et al[2] reported Ritonavir associated retinal pigment epitheliopathy in three
patients. We report a patient on Ritonavir for seven years who presented with
decreased vision concomitantly with mild liver dysfunction. Outer retinal
abnormalities were seen on spectral-domain optical coherence tomography
(SD-OCT) that markedly improved within two weeks of discontinuation of Ritonavir.
No abnormalities were seen on fundus autofluorescence (AF) and fluorescein
angiogram (FA). The study was approved by institutional review board by New
Jersey Medical School, University of Medicine and Dentistry of New Jersey (merged into Rutgers University in 2012).
A 47-year-old HIV-positive
man was referred to our institution for progressive visual loss and central
relative scotoma for two weeks in the left eye. His past medical history
included HIV infection (for 7y), hypothyroidism, and hypercholesterolemia. He
denied any history of tobacco or alcohol abuse. The CD4+ T-cell count was 438
cells per microliter with undetectable HIV-1 RNA. He had no history of
AIDS-defining diseases. He had been on the HAART therapy for 6y since the
diagnosis of HIV which included Epzicom (abacavir + lamivudine) 600 mg/300 mg
daily, Lexiva (fosamprenavir) 1400 mg daily, and Norvir (Ritonavir) 200 mg
daily. Mild liver dysfunction was seen two months before visual
symptoms started: increased aspartate aminotransferase (AST)
at 51 U/L (normal <40 U/L). Abnormal lipid profile had also been noted in
the previous 3mo: elevated serum cholesterol (268 mg/dL; normal <200
mg/dL), and decreased high-density lipoproten (HDL) (48 mg/dL; normal >55
mg/dL).
On examination, the best corrected visual acuity (BCVA) was
20/25 in the right and 20/400 in the left eye with a central scotoma confirmed
by confrontation
visual field exam. Anterior exam of both eyes
was normal without any uveitis or vitritis. Posterior segment examination
revealed a 400-μm circular,
slightly hyperemic lesion centered at the left fovea (Figure 1A). SD-OCT
revealed thickened and irregular retinal pigment epithelium (RPE) with
overlying loss of inner/outer segment junction layer
(IS/OS) integrity in the foveal area; the external limiting membrane (ELM) was
intact but slightly irregular (Figure 2A). The AF showed no abnormalities. The
FA showed no hypo- or hyperfluorescence in the foveal area or elsewhere.
Possibility of Ritonavir ocular toxicity was suspected in light of recent liver
abnormalities; Ritonavir has hepatic clearance. Ritonavir was discontinued
immediately after consulting his infectious disease physician. BCVA (Snellen)
improved from 20/400 to 20/25 within 2wk. Humphrey visual field (HVF) showed a
smaller central scotoma with a mean deviation (MD) of -3.79 (P<0.02) (Figure 3). The macular examination showed resolution of the foveal hyperemic lesion (Figure 1B). OCT of the macula improved; RPE layer had normalized
with less disrupted and smoother IS/OS layer and a normal
ELM (Figure
2B). The results of laboratory work-up 2-week later revealed rapid plasmin reagan (RPR) titer 1:64 confirmed with a
reactive fluorescent treponemal antibody absorption (FTA-Abs), erythrocyte
sedimentation rate (27, 0-10 mm/h), negative Bartonella antibody panel,
toxoplasma IgM and IgG antibody titers and a normal chest X-ray. On the basis
of positive syphilis titers, intravenous penicillin treatment was initiated
(this was 3wk after Ritonavir was stopped and and improved visual acuity was
documented to 20/25 and marked improvement of OCT was documented before the
syphilis treatment was initiated). Subsequent visits showed improvement in
macular exam, and on HVF. OCT was normal with
well-defined IS/OS layer and ELM (Figure 2C) 6wk after Ritonavir was discontinued. Follow-up
visit 6mo later revealed, BCVA of
left eye
stable at 20/25 with a normal macular exam, AF, FA and OCT.
Figure 1 Color fundus photographs of the left eye at
presentation (A) and 2wk after discontinuation of Ritonavir (B).
Figure 2 SD-OCT examination
of the left eye at presentation (A), 2wk after discontinuation of Ritonavir(B),
and 6wk after discontinuation
of Ritonavir (C).
Figure 3 HVF examination
of the left eye 2wk (A) and 4wk (B) after discontinuation of Ritonavir.
The patient presented with
retinal pigment epitheliopathy which was attributed to Ritonavir toxicity in
the presence of abnormal liver function tests (LFTs). The epitheliopathy
resolved within 2wk of discontinuation of Ritonavir. Syphilis titers were
reported to be positive and pencillin treatment was initiated 3wk after
discontinuation of ritonovir. Posterior placoid chorioretinitis has been
reported with syphilis[3]; however, we do not believe the macular findings in our patient were
syphilis related, in light of improvement in clinical examination, visual
acuity to 20/25 and SD-OCT before the syphilis treatment was started; Ritonavir
is more likely to be the culprit. Also, the FA of our patient lacked the
typical late staining that is noted with placoid chorioretinitis[4].
Roe et al[2] recently reported three cases of retinal pigment epitheliopathy in
HIV-positive patients receiving Ritonavir. Ritonavir is 99% protein bound and
metabolized in the liver through cytochrome P-450 pathways. Ritonavir toxicity
is dose-related. It was showed that even a moderate liver impairment would
double its serum level[2]. It is prudent to believe mild liver dysfunction 2mo prior to ocular
symptoms in our patient would be the triggering event which caused Ritonavir serum
levels increased to Ritonavir toxic level; even though it had been well
tolerated for the previous six years. In contrast to three
patients in Roe et alÕs report[2], RPE changes in our
patients were
unilateral, mild and transient. It may be a reflection of an early diagnosis of
RPE toxicity in our case such that the changes were reversible with a rapid
improvement in visual acuity and clinical findings with
discontinuation of the drug.
ACKNOWLEDGEMENTS
Conflicts of Interest: Tu Y, None; Poblete
RJ, None; Freilich BD, None; Zarbin MA, None; Bhagat N, None.
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