Retinal Toxicity During Pegylated Alfa Interferon Therapy for
Chronic Hepatitis C
By Ronald Baker, PhD
There have
been documented and anecdotal reports of ocular side effects during
therapy with
pegylated interferon and ribavirin. The aim of the current study was
to evaluate the effect of therapy with pegylated interferon and
ribavirin on the eyes of patients with
chronic hepatitis C.
In this small
study, 10 patients receiving
peginterferon alfa-2a (Pegasys) and ribavirin and 10 healthy
volunteers underwent full ophthalmic investigations and multifocal
electroretinogram testing at baseline, and at regular intervals during
treatment and post-treatment. The multifocal electroretinogram maps
retinal function. Responses were compared with sequential recordings
from healthy volunteers.
Results
All patients had normal
clinical ophthalmic investigations at baseline. During therapy a
single patient experienced central visual disturbance lasting 24 h
with no prolonged ill effect.
No other patient was
aware of any change in vision.
Fundal abnormalities
[relating to the retinal area] appeared in five patients during
treatment.
The multifocal
electroretinogram showed reductions in retinal function in five
patients.
Nine of 10 patients
exhibited abnormalities on at least one multifocal electroretinogram
or fundoscopic investigation.
The authors
conclude, "Subclinical retinal toxicity during anti-viral therapy with
pegylated alpha-interferon and ribavirin was frequent in this study and
it suggests that patients should be warned of this risk and monitored
during therapy."
Department of Clinical
Physics and Bioengineering, Gartnavel General Hospital, Glasgow, UK.
See also
Is Screening for Peginterferon-related Retinopathy in Hepatitis C
Justified? and
Treatment with Pegylated Interferon May Cause Eye Complications
in Patients with Chronic Hepatitis C
Commentary
Serious ocular
disorders do not appear to occur frequently among patients using
standard interferon or the peginterferons plus ribavirin. However,
such problems can occur. If vision problems develop, patients should
immediately call their physician and set up an appointment to see an
ophthalmologist for a complete eye examination.
The product
information on the pegylated interferons contains a warning about
potential ophthalmologic disorders. The following text is excerpted from
the WARNINGS section of the Pegasys Product Information (9).
There is a similar WARNING on potential ocular disorders
associated with peginterferon alfa-2b in the Peg-Intron/Rebetol
product information:
“Decrease or loss of
vision, retinopathy including macular edema, retinal artery or vein
thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis,
and papilledema are induced or aggregated by treatment with PEGASYS or
other alpha interferons.
“All patients should
receive an eye examination at baseline. Patients with preexisting
opthalmologic disorders (e.g., diabetic or hypertensive retinopathy)
should receive periodic opthalmologic exams during interferon alpha
treatment. Any patient who develops ocular symptoms should receive a
prompt and complete eye examination.
“Pegasys treatment
should be discontinued in patients who develop new or worsening
ophthalmologic disorders.” [emphasis added]
Selected Excerpts from
the Literature on Retinal Toxicity Related to Therapy with Standard
Interferon and/or Pegylated Interferon:
“The incidence of
serious ocular pathology associated with anti-HCV therapy may be very
high and is probably associated with peg-IFN alpha-2b. Increased
monitoring of patients treated with peg-IFN alpha-2b for retinal and
visual changes is warranted.” C Farel et al (3).
“Although ocular
toxicity is uncommon, it should be emphasized that it can occur any time
after the start of interferon therapy, and physicians now treating
chronic hepatitis C patients with pegylated interferon must be aware of
this potentially serious adverse event.” RA Willson (8).
The multifocal
electroretinogram can detect retinal dysfunction in chloroquine
retinopathy even when the full-field electroretinogram is normal and
retinal alterations are subtle. Kellner et al (5).
“This case report
underlines the necessity of an EOG on patients with INF-alpha therapy.
Until now, the pathogenesis of this retinal toxicity has been poorly
understood. These results show that the retinal pigmented epithelium is
probably implicated at an early stage in this retinal toxicity.” M
Crochet et al (2)
“Subclinical retinal
toxicity during anti-viral therapy with pegylated alpha-interferon and
ribavirin was frequent in this study and it suggests that patients
should be warned of this risk and monitored during therapy.” Chisolm et
al (1)
‘Subclinical
neurovisual impairment is a frequent, largely unrecognized complication
of low-dose IFN therapy, and patients with chronic hepatitis B and older
age appear to be most susceptible. This apparently innocuous
complication is long lasting, possibly irreversible in some patients,
with yet undetermined consequences on visual function.” Manesis et al
(6)
“8/19 patients, while
on treatment, developed an asymptomatic retinopathy. Among these 3/8
were relapsers and 5/9 were non-responders to interferon monotherapy.
All retinal changes faded, often while the patients continued the
therapy. There was no significant association in occurrence of
retinopathy with haematological and/or biochemical changes.” Jain et al
(4)
“Although ocular
toxicity is uncommon, it should be emphasized that it can occur any time
after the start of interferon therapy, and physicians now treating
chronic hepatitis C patients with pegylated interferon must be aware of
this potentially serious adverse event.” Willson (8)
04/06/05
Citations
(1) J A Chisholm and
others. Retinal toxicity during pegylated alpha-interferon therapy for
chronic hepatitis C: a multifocal electroretinogram investigation.
Alimentary Pharmacology & Therapeutics. 21(6): 23-32. March 15,
2005.
(2) M Crochet and
others. Retinopathy caused by interferon alpha associated with ribavirin
therapy and the importance of the electro-oculogram: a case report.
Journal of French Ophthalmolology 27(3):257-262. March 2004.
(3) C Farel and
others. Serious ophthalmic pathology compromising vision in HCV/HIV
co-infected patients treated with peginterferon alpha-2b and ribavirin.
AIDS 18(13):1805-9. September 3, 2004.
(4). K Jain and
others. Retinopathy in chronic hepatitis C patients during interferon
treatment with ribavirin. British Journal of Ophthalmology
85(10):1171-3. October 2001.
(5). U Kellner, Kraus
H, Foerster MH.. Multifocal ERG in chloroquine retinopathy:
regional variance of retinal dysfunction. Graefe's Archive for
Clinical and Experimental Ophthalmology 238(1): 94-97. January 2000.
(6). E K Manesis and others. Neurovisual impairment: a frequent
complication of alpha-interferon treatment in chronic viral hepatitis.
Hepatology 27(5):1421-7. May 1998.
(7). A Tsolakos and N
Zalatimo. Hepatitis C: a review of diagnosis, management, and ocular
complications from treatment. Optometry 74(8): 517-23. August
2003.
(8). R A Willson.
Visual side effects of pegylated interferon during therapy for chronic
hepatitis C infection.
Journal of Clinical
Gastroenterology
38(8): 717-722. September 2004.
(9). Hoffman-La Roche.
WARNINGS: Ophthalmologic Disorders. Pegasys Product Information. Page
10. January 2004.
Ophthalmological Side Effects of Hepatitis C Treatment are Related
to Vascular Endothelial Growth Factor Levels
Ophthalmological
side effects, including vision problems, are sometimes reported by
patients receiving interferon-based therapy for chronic hepatitis C.
To determine the
incidence and cause of these adverse events, researchers prospectively
screened interferon-treated patients for vascular ophthalmological side
effects, and looked for evidence of activation of angiogenesis
(proliferation of new blood vessels).
The study
included 34 chronic hepatitis C patients; 18 were treated with
180 micrograms/week of pegylated interferon alfa-2a (Pegasys) plus 800
mg/day of ribavirin, while 16 received
1.5 micrograms/kg/week of pegylated interferon alfa-2b (Peg-Intron) plus
800-1200 mg/day of ribavirin.
Complete
ophthalmological evaluation and serum levels of vascular endothelial
growth factor (VEGF) -- a cytokine that promotes blood vessel
proliferation -- were assessed before and at the end of therapy.
Results
13 patients (38.2%)
developed vascular ophthalmological side effects during interferon
therapy; 8 patients (23.5%) developed subconjunctival hemorrhage,
and 5 (14.7%) had evidence of retinopathy.
In 3 of the 13
patients, visual acuity was affected, and 2 had residual lesions
during post-treatment follow-up.
These side effects were
not associated with age, sex,
HCV genotype, antiviral schedule, type of interferon, or
response to therapy.
At the end of
treatment, the group with vascular ophthalmological side effects had
significantly higher serum VEGF levels than the group without
detectable ophthalmological side effects (281 vs 117 pg/mL; P =
0.05).
These differences
increased when VEGF values were adjusted for platelet count.
In the ophthalmological
side effects group, baseline VEGF (164 vs 64 pg/mL, P = 0.046) and
VEGF/platelet values (0.920 vs 0.320 pg/106 platelets, P = 0.024)
were also significantly higher.
In a multivariate
model, VEGF/platelet values at the end of treatment and
hepatic fibrosis stage were the only predictors of vascular
ophthalmological side effects.
Conclusion
The authors
concluded that in this exploratory study, antiviral therapy for chronic
hepatitis C "frequently induces vascular ophthalmological side effects,
apparently through an activation of angiogenesis."
7/21/06
Reference
R J Andrade, F J Gonzalez, L Vazquez, and others. Vascular
ophthalmological side effects associated with antiviral therapy for
chronic hepatitis C are related to vascular endothelial growth factor
levels. Antiviral Therapy 11(4): 491-498. 2006.
OPHTHALMOLOGIC EFFECTS
A
variety of visual changes can occur among patients treated with
interferon-based
therapy, including retinal hemorrhage, vision changes, and vision loss.1
Ophthalmologic
toxicity of interferon is usually reversible, but consideration should
be given to treatment
discontinuation when it occurs. Any patient with ophthalmologic symptoms
should be
sent
for an ophthalmology consult.
PATHOPHYSIOLOGY
The
underlying pathogenesis of retinopathy associated with interferon is not
clear and
is probably multifactorial. Lohmann et al2
reports that although
the mechanism of
interferon-associated anterior ischemic optic neuropathy is unclear, it
is most likely to be
linked
to an immunologic process. It has been postulated that interferon alfa
is able to
produce
autoantibodies, and subsequently causes deposition of immune complexes
in
the
small retinal or optic nerve arteries. Interferon is also an
immunomodulator that
stimulates other cytokines, such as various interleukins, and
upregulates
histocompatibility complex class II proteins. These interleukins can
cause an
inflammatory reaction of the blood vessels and lead to ischemia.
Unfortunately, such
ischemia and vision loss may be permanent. The incidence of
ophthalmologic
complications does not seem to be influenced by the type or dose of
interferon. However,
there
is a reported higher incidence of complications in patients with certain
clinical
entities, specifically diabetes, hypertension, retinal arterial
sclerosis, and anemia.3
High
levels
of low-dose lipoprotein cholesterol and atherosclerotic index may also
influence
the likelihood of the development of retinopathy.3
There
may be a physiologic relationship between the presence of retinal
complications
and
levels of plasma-activated complement 5 (C5a), which is a known potent
intravascular aggregator of granulocytes.4,5
In specific clinical
studies, when retinal
hemorrhage occurred, C5a levels were significantly increased. A high C5a
level may be
an
important step in the pathogenesis of retinal capillary infarction,
microvascular
emboli,
hemorrhage, and cotton wool spot formation.
The
time of onset after administration is nonspecific, though there are
reports of patients
with
HCV infection who have experienced retinal hemorrhage and/or cotton wool
spots
early in the course of therapy (ie, within the first 8 weeks).3
There seems to be no
relationship between the incidence of retinopathy and the levels of
liver enzymes, but
increased incidence is reported in patients after the WBC and the
platelet count have
reached
a nadir. Sudden bilateral visual loss with disc-related field defects
and segmental
optic
disc edema has been reported but is rare. Permanent loss of vision is
thought to be a
result
of closure of the retinal capillaries.
In a Japanese study,6
50 patients treated
with interferon for chronic HCV, HBV, or renal
cell
carcinoma were examined for retinal complications. Retinal hemorrhages
or cotton
Side Effects Management
Handbook • X.
Neurologic/Ophthalmologic • p. 15
wool
spots were observed in 23 patients (46%). Hemorrhage without cotton wool
spots
was
found in 14 patients, cotton wool spots without hemorrhage in 5
patients, and both
conditions in 4 patients. These findings were potentially reversible.
There was one case
of
branch retinal artery occlusion and one case with micro-aneurysm. RBC
decreased
significantly in patients with retinopathy compared with those without
retinopathy
(P
<.05%). In another study,7
cotton wool spots
disappeared after interferon treatment
was
stopped and they did not return unless interferon therapy was restarted.
However, in
three
cases, the cotton wool spots disappeared despite continued therapy.
These cases
emphasize the need for careful retinal surveillance of patients treated
with interferon to
diagnose this potentially reversible retinal ischemia.
Special
note: Patients with chronic HCV are known to have circulating immune
complexes, and patients with hypertension and/or diabetes have been
shown to have
damage to endothelial cells, retinal ischemia, and capillary
nonperfusion.8
It may be in
this
population of patients, in whom this combination of factors exists, that
the most
severe
problems are more likely to be seen.
BASELINE TESTS RECOMMENDED9
·
Ocular
examination, including:
·
Photographic
documentation
·
Recording of
visual evoked responses (VERs)
·
Electroretinograms
·
Visual acuity
·
Visual fields
All
healthcare providers should be aware of potential risk to patients
treated with
interferons. Patients without conditions predisposing to vascular
nonperfusion should be
followed closely and visual complaints investigated thoroughly.8
Delayed clinical
diagnosis or delays in follow-up of subjective complaints are likely to
be associated with
poor
visual outcomes.
COMMON SUBJECTIVE SYMPTOMS* FREQUENTLY NOTED CLINICAL FINDINGS1-3,7,8,10-12
·
Abnormal vision
·
Latency in VERs
·
Blurred vision
·
Subconjunctival hemorrhage
·
Diplopia
·
Cotton wool spot formation
·
Dry eyes
·
Retinopathy
·
Eye pain
·
“Splinter hemorrhages”
·
Nystagmus
·
Macular edema
·
Photophobia
·
Optic tract neuropathy
·
Vision loss
·
Capillary nonperfusion
·
Coinfected patients: vision changes, loss
·
Anterior ischemic optic neuropathy
·
Rule out CMV retinitis
*Patients may be asymptomatic early in
treatment.
Side Effects Management
Handbook • X.
Neurologic/Ophthalmologic • p. 16
TREATMENT STRATEGIES2,11,13
1.
Discontinue interferon-based therapy. After discontinuation,
treatment-associated
neurovisual abnormalities may resolve. There are reports of persistent
complications,
so
careful monitoring of patients is required. If the physician elects to
resume
interferon therapy; advise him/her to obtain a letter of clearance from
an
ophthalmologist.
2.
Obtain a CBC with differential.
3.
Consider aspirin and prednisone for anterior ischemic optic neuropathy.
4.
Recommend, for local symptomatic relief:
a.
Artificial tears/lubricants
b. Cool
cloths over eyes
c.
Reduced exposure to light: close blinds/drapes, dim lights, use
sunglasses
5.
Recognize that patients with a history of CMV retinitis will commonly
relapse during
antiviral therapy.
Special
Note:
1. Postliver transplantation symptomatic complications can occur.14
2.
Ocular complications have been reported in 2% of patients with 65% of
these being
opportunistic infections such as14:
a.
Herpes viral retinitis
b.
Fungal chorioretinitis
c.
Central retinal vein occlusion
d.
Herpes zoster ophthalmicus
e.
Herpetic keratitis
f.
Cyclosporine retinopathy
3.
There are reported clinical trials of interferon alfa-2a for the
treatment of choroid
neovascularization membranes.10
REFERENCES
1. Kadayifcilar S, Boyacioglu S, Kart H,
Gursoy M, Aydin P. Ocular complications with highdose
interferon alpha in chronic active
hepatitis. Eye. 1999;13:241-246.
2. Lohmann CP, Kroher G, Bogenrieder T,
Spiegel D, Preuner J. Severe loss of vision during
adjuvant interferon alfa-2b treatment for
malignant melanoma. Lancet. 1999;353:1326.
3. Kawano T, Shigehira M, Uto H, et al.
Retinal complications during interferon therapy for
chronic hepatitis C. Am J Gastroenterol.
1996;91:309-313.
4. Sugano S, Suzuki T, Ishii K, et al.
Elevated plasma C5a levels as a possible risk factor of
retinal bleeding during interferon-alfa
therapy for chronic hepatitis C. Hepatology. 1996;24
(4 part 2):277.
5. Sugano S, Suzuki T, Watanabe M, Ohe K,
Ishii K, Okajima T. Retinal complications and
plasma C5a levels during interferon alpha
therapy for chronic hepatitis C. Am J
Gastroenterol.
1998;93:2441-2444.
6. Chuman T, Nao-i N, Sawada A, Kawano T,
Shigehira M. Interferon-induced retinal changes.
Journal of Japanese
Ophthalmology.
1994;98:616-621.
7. Guyer DR, Tiedeman J, Yannuzzi LA, et
al. Interferon-associated retinopathy. Arch
Ophthalmol.
1993;111:350-356.
8. Chambers RB, Downie A, Foote B, Davidorf
FH. Interferon alfa-associated retinopathy. J Am
Osteopath Assoc.
1997;97:43-45.
Side Effects Management
Handbook • X.
Neurologic/Ophthalmologic • p. 17
9. Manesis EK,
Moschos M, Brouzas D, et al. Neurovisual impairment: a frequent
complication
of alpha-interferon treatment in chronic
viral hepatitis. Hepatology. 1998;27:1421-1427.
10. Thoelen A, Menozzi M, Huber C, Messmer
E. Treatment of choroidal neovascularization in
age-related macular degeneration with
interferon alpha-2a: a short term, nonrandomized pilot
study. Geriatric Journal of
Ophthalmology. 1995;4:137-143.
11. Purvin VA. Anterior ischemic optic
neuropathy secondary to interferon alfa. Arch
Ophthalmol.
1995;113:1041-1044.
12. Shahidullah AB, Cerulli MA, Berman DH.
Interferon may cause retinopathy during hepatitis
therapy. Am J Gastroenterol.
1995;90:1543.
13. Woodruff R. Symptom Control in
Advanced Cancer. Melbourne, Australia: Asperula Pty Ltd;
1997:90-91.
14. Ng P, McClusky P, McCaughan G,
Glanville A, MacDonald P, Keogh A. Ocular
complications of heart, lung, and liver
transplantation. Br J Ophthalmol. 1998;82:423-428.
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