Optometry - Journal of the American Optometric Association
Volume 81, Issue 11 , Pages 580-586, November 2010

Retinopathy associated with pegylated interferon and ribavirin treatment for chronic hepatitis C

  • Shelly Adams, O.D.

      Affiliations

    • Corresponding Author InformationCorresponding author: Shelly Adams, O.D., Veterans Affairs Southern Oregon Rehabilitation Center & Clinics, Optometry, 8495 Crater Lake Hwy, White City, Oregon 97503.
    • ,
  • Mark Ostermeier, O.D.

Veterans Affairs Southern Oregon Rehabilitation Center & Clinics, White City, Oregon

published online 26 July 2010.

Article Outline

Abstract 

Background

Retinopathy is associated with the use of interferon and ribavirin for the treatment of chronic hepatitis C. Common ocular complications include cotton wool spots, retinal hemorrhages, and macular edema.

Case Report

A 53-year-old black man with a history of drug and alcohol abuse was admitted to the Department of Veterans Affairs clinic for substance abuse treatment. Results of a liver biopsy showed chronic hepatitis C, and treatment with interferon and ribavirin was initiated. A comprehensive eye examination was performed just before the initiation of treatment, and the patient was then periodically monitored for the presence of retinopathy. No retinopathy was found at the initial visit or at his 1-month or 2-month follow-up examinations. His 4-month retinal evaluation found cotton wool spots in both eyes and retinal hemorrhages in the left eye. The retinopathy persisted for several months but resolved in both eyes before his treatment was discontinued. Throughout his treatment period there were no visual complaints or visual acuity changes.

Conclusions

Although this patient was visually asymptomatic, and his retinopathy resolved during treatment, we chose to monitor the patient monthly during treatment because of the risk of serious (although rare) ocular complications.

Keywords: Hepatitis C, Ribavirin, Pegylated interferon, Retinopathy

 

Infection with hepatitis C virus (HCV) is one of the leading causes of liver disease in the United States.1, 2 Worldwide, it is estimated that HCV affects 170 million people, with a higher prevalence in Asia (including Korea and Japan) than in Europe or the United States.3, 4 Within the United States, approximately 4.1 million people have antibodies to HCV, which indicates an ongoing or previous infection with the virus.5 HCV accounts for about 15% of acute viral hepatitis, 60% to 70% of chronic hepatitis, and up to 50% of cirrhosis, liver cancer, and end-stage liver disease within the United States.5 Annually, it causes an estimated 10,000 to 12,000 deaths in the United States.5

Current treatment for HCV includes a 24- or 48-week course of pegylated interferon in combination with ribavirin, with the length of treatment based on the specific HCV genotype contracted. Retinopathy secondary to the combination therapy is characterized most commonly by retinal hemorrhages, cotton wool spots, and macular edema.6 Retinopathy is usually transient and disappears during the course of the treatment. Although infrequent, serious ocular complications, such as optic disc edema and retinal vein occlusions, can occur with interferon and ribavirin treatment. In these cases, treatment may need to be discontinued early and those complications addressed. Although guidelines are proposed for the frequency of retinal examinations during interferon treatment for HCV, no consensus has been reached.

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Case report 

A 53-year-old black man with a history of drug and alcohol abuse was admitted to the Department of Veterans Affairs (VA) rehabilitation center in July 2008 for substance abuse treatment. By age 10 he started smoking, and by age 13 began drinking alcohol and using illicit drugs, including marijuana, cocaine, heroin, and various stimulant pills. He started using drugs intravenously in his 20s. There was a history of gonorrhea decades ago. Within the year before his admission to the VA rehabilitation center, he had used cocaine, alcohol, and marijuana.

A liver biopsy specimen was taken, and the results found chronic HCV with mild activity (his genotype was identified as 1a) and portal-periportal fibrosis (Batts-Ludwig grade 2, stage 2). The patient was given the option of no treatment with careful monitoring, starting treatment with interferon and ribavirin, or waiting for treatment until the new protease inhibitors become available. The patient chose to start treatment with interferon and ribavirin. He was started on a 48-week treatment regimen of 180 μg of pegylated interferon (peginterferon) α-2a injections given subcutaneously weekly and 500 mg ribavirin given orally twice daily. At the start of the treatment his weight was 186 lbs.

Five days before the start of treatment, the patient was seen in the optometry clinic for a comprehensive eye examination. He presented with no visual complaints except that his eyes occasionally felt mildly irritated. He was only using over-the-counter reading glasses at the time but expressed interest in switching to bifocals. His ocular history was positive for sustaining lacerations above both eyes from trauma, which required sutures. He had also been monitored in the past for suspected glaucoma. Uncorrected distance visual acuities were 20/20− in the right eye (O.D.) and 20/25+ in the left eye (O.S.). Pupils were equal, round, and reactive to light, with no afferent defect. Extraocular motilities and confrontation visual fields were full in both eyes. Cover testing findings were unremarkable. Refraction found −0.25 diopters sphere O.D. and plano −0.50 × 090 O.S. with acuities of 20/20 O.D. and O.S. Biomicroscopy was unremarkable with the exception of pingueculae in both eyes (OU) and trace nuclear sclerotic lens changes OU. A dilated examination found no macular edema or retinopathy in either eye. Optic cup size was estimated at 0.65 round O.D. and 0.6 round O.S., and artery-to-vein ratios were estimated at 2/3 OU. Vitreous and retina were clear in both eyes. Goldmann applanation tonometry readings were 14 mmHg O.D. and 15 mmHg O.S. at 1:15 p.m. The patient was advised to return in 1 month for a retina check and (updated) visual fields.

Retinal examination 1 month and 2 months after the start of interferon and ribavirin treatment found no retinopathy, and the patient had no visual complaints. Uncorrected visual acuities were 20/20− O.D. and 20/20− O.S. at both visits. He did report significant systemic adverse reactions to the medication including headache, myalgia, joint pain, depression, dry skin, dry mouth, nasal congestion, pruritis, anxiety, weakness, irritability, and lack of motivation. Two weeks after the initiation of treatment he reported a pain level of 5 (on a scale of 1 to 10) for his headache and generalized joint and muscle pain, which increased to nine 3 weeks later. Three months after initiation of treatment his polymerase chain reaction (PCR) results showed no detectable virus.

Retinal examination 4 months after the start of treatment found multiple cotton wool spots in the posterior pole OU and retinal nerve fiber layer hemorrhages superior and inferior to the optic nerve O.S. (see Figure 1, Figure 2). Maculae were flat with no edema in either eye. An updated refraction showed no change from the pretreatment visit, and acuities were 20/20− O.D. and 20/20 O.S. Complete blood count values indicated anemia, neutropenia, and thrombocytopenia.

One month later (5 months after starting treatment), retinal evaluation found resolving cotton wool spots OU, with no retinal hemorrhages (see Figure 3, Figure 4). Again, there were no signs of macular edema, and uncorrected acuities were 20/20− OU. At the 6-month follow-up examination, the retinopathy had resolved in the left eye, and the right eye had trace cotton wool spots, along with 2 retinal hemorrhages, one in the superior arcade, and one superior to the disc (see Figure 5, Figure 6). His retinopathy had resolved in the right eye by the time his treatment was prematurely discontinued because of the development of a pulmonary lesion and suspicion of neoplastic disease (this occurred 27 weeks into a planned 48-week treatment period). His weight had decreased to 171 lbs when the treatment was stopped. The patient had no visual complaints throughout the course of his treatment.

  • View full-size image.
  • Figure 5 

    Six months after initiation of treatment: trace cotton wool spots with 2 nerve fiber layer hemorrhages, 1 in the superior arcades and 1 superior to the optic nerve O.D.

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Discussion 

Hepatitis C virus 

HCV was first identified in 1989; it is a small enveloped, single-stranded RNA virus of the family Flaviviridae.5 The virus mutates rapidly, which may help it evade the immune system because of changes in the envelope proteins.5 There are at least 6 major genotypes of HCV, with genotype 1a and 1b being the most common in the United States (75% of cases).5 Genotypes 2 and 3 are present in 10% to 20% of patients.5 Although there is little difference in the severity of disease or outcome of patients infected with different genotypes, genotypes 2 and 3 are more likely to respond to treatment with interferon.5 Numerous clinical studies have found that 50% to 60% of HCV patients with genotype 1, 20% of patients with genotypes 2 and 3, and 30% to 40% of patients with genotype 4 are not cured by the current standard treatment.7, 8, 9, 10, 11, 12

HCV is acquired primarily by contact with infected blood and blood-related products.5 Blood transfusions were a common source of infection up until the early 1990s, when sensitive blood screening tests for HCV antibody were introduced.5, 7 Today, the most common cause of infection is from drug use with shared, unsterilized, or poorly sterilized needles and syringes.5 Other risk factors include hemodialysis for kidney failure, needle-stick accidents, birth from an HCV-infected mother, sex with an HCV-infected partner, and intranasal use of cocaine using shared equipment.5

HCV is rarely diagnosed during the acute stage because of a lack of specific symptoms, and it is assumed that 20% to 30% of patients clear the virus spontaneously within 6 months of initial infection.7 Chronic HCV is diagnosed when antibodies are present, and serum aminotransferase levels remain elevated for more than 6 months.5 Testing for HCV RNA is done with the PCR test, which confirms the diagnosis and the presence of viremia.5 If diagnosed in the acute stage, HCV can be cured in most cases; however, chronic HCV is resistant to treatment almost half of the time.7

Interferon and ribavirin 

Interferon has been approved for use in the treatment of viral and malignant diseases, including hepatitis, multiple sclerosis, leukemia, AIDS-related Kaposi's sarcoma, and malignant melanoma. It is a complex group of proteins that have antiviral, antiproliferative, and immunomodulatory activity.13 Pegylated (polyethylene glycol conjugated) interferon is a long-acting form of interferon. It has slower absorption, a reduced volume of distribution, and lower elimination rates, and it yields a higher and more sustained clearance rate than nonpegylated interferon (50% to 60% compared with 12% to 16%).6, 14 Pegylated interferon is given subcutaneously in a fixed dose of 180 μg per week (for α-2a) or subcutaneously in a weight-based dose of 1.5 μg per kilogram (for α-2b) once per week.5

Ribavirin is an oral antiviral agent that has activity against a broad range of viruses.5 It is a synthetic guanosine nucleoside analog that inhibits both DNA and RNA viruses and has immunoregulatory activity.13, 15, 16 By itself, ribavirin does not have much effect on HCV, but adding it to interferon increases the sustained response rate by 2- to 3-fold (a response is considered sustained if HCV RNA remains undetectable for 6 months or more after stopping therapy).5 Ribavirin is given orally twice daily in capsule form in a weight-based dose of 800 to 1,200 mg/d.7

Combination therapy (interferon and ribavirin) leads to the disappearance of detectable HCV RNA in up to 70% of patients.5 During treatment, some patients who become HCV RNA negative will relapse when therapy is stopped, but the relapse rate is lower in patients treated with combination therapy compared with monotherapy.5 For patients treated with combination therapy, a treatment course of 48 weeks is recommended for those with genotype 1.5 However, for patients with genotypes 2 and 3, a treatment course of 24 weeks is recommended because genotypes 2 and 3 are more likely to respond to treatment.5

Common side effects of interferon therapy include fatigue, muscle aches, headaches, nausea and vomiting, skin irritation at the injection site, low-grade fever, weight loss, irritability, depression, mild bone marrow suppression, and hair loss (reversible).5 Common side effects of ribavirin include anemia, fatigue and irritability, itching, skin rash, nasal stuffiness, sinusitis, and cough.5 Hemolytic anemia is a universal event associated with ribavirin combination therapy caused by the hemolysis of red blood cells (this causes the hematocrit to decrease by 5% to 10%), although the extent of anemia can vary greatly between individuals.5, 17 Premature withdrawal from therapy or dose reduction is sometimes necessary because of adverse effects from the combination therapy.

Retinopathy associated with hepatitis C treatment 

Since the first case of retinopathy associated with the treatment of HCV was reported in 1990 by Ikebe et al.,19 many other cases have been reported.3, 18, 19 The most common retinal findings are cotton wool spots and/or retinal hemorrhages, which may occur alone or together.20, 21, 22 The retinopathy is generally mild and usually resolves completely during therapy or quickly after therapy and frequently occurs without visual symptoms.20, 23, 24

Although rare, other ocular complications secondary to treatment for HCV have been reported including cystoid macular edema, subconjunctival hemorrhage, neovascular glaucoma, anterior ischemic optic neuropathy, optic disc edema, retinal detachment, retinal vein thrombosis, intraocular hemorrhage, epiretinal membrane, severe loss of vision, blindness, permanent monocular visual field defect, and retinal vein and artery occlusion.3, 14, 18, 21, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 One case of severe retinopathy was reported in a hypertensive patient treated with interferon for multiple myeloma.23 Serious complications are rare and may represent coincidental events.24

The incidence of retinopathy associated with interferon treatment varies widely in the literature, from 15% to 80% in one report to 18% to 86% in others.3, 6, 13, 14, 20, 24, 36, 37 In some studies, the reported incidence may be falsely low; because the retinopathy is usually transient it may not have been detected if retinal examinations were not performed regularly.20, 33, 38

Some findings suggest that diabetes or systemic hypertension may be a risk factor for the development of retinopathy during interferon therapy.3, 14, 36, 39, 40 Patients with diabetes and hypertension may be at risk for the development of retinopathy during interferon therapy because of preexisting disturbances in their retinal microcirculation.14 Other studies have concluded that patients with diabetes or hypertension are probably not at [increased] risk for interferon-induced retinopathy.1

Ribavirin is not used as monotherapy for the treatment of any medical condition, so the effects of ribavirin alone on retinopathy are unclear.14 However, the incidence of retinopathy is higher in those treated for HCV (usually combination therapy of interferon and ribavirin) than those treated for hepatitis B (usually monotherapy of interferon), so ribavirin may be a factor in this increased incidence.14 Retinal hemorrhages with white centers (Roth's spots) can occur with HCV treatment and may be associated with ribavirin-induced hemolytic anemia. Retinopathy caused by anemia is most likely to occur in patients with severe anemia or when thrombocytopenia is coexistent.41, 42

The underlying mechanism responsible for interferon-associated retinopathy is not well understood.1, 6, 14 Some investigators suggest that immune complex deposition causes occlusion of retinal capillaries, which then leads to the formation of cotton wool spots.1, 6, 23, 43 An ischemic mechanism similar to that seen in hypertensive and diabetic patients has also been suggested.1, 6 Interferon has also been found to induce leukocyte capillary trapping in rat retinal microcirculation.23, 44 One clinical study suggests impairment of endothelial function because flow-mediated vasodilation in the brachial artery decreased in patients with chronic HCV treated with interferon.45, 46 Nagaoka et al.45 evaluated the effects of interferon therapy on retinal microcirculation and found that the patient's age and a change in wall shear rate (WSR), which is an index of wall shear stress (WSS), were risk factors for the development of interferon-associated retinopathy.45 (WSS equals the viscosity times the WSR and is the tangential stress induced by the blood flow across the endothelial cells of the arterial wall.47) The results of the study by Nagaoka et al.45 showed that retinal blood flow increases in association with interferon therapy in patients with chronic HCV, and they found significant differences in the changes in diameter, velocity, and WSR between patients with and without interferon-associated retinopathy. Because WSS should remain constant under physiologic conditions, Nagaoka et al.45 concluded that the increase in WSR in patients with retinopathy indicates that endothelial dysfunction may play an important role in the development of retinopathy in those treated with interferon.

Various conclusions have been drawn from the available studies with regard to the recommended frequency of retinal examinations for patients on interferon therapy for HCV. Some investigators have concluded that routine retinal examinations may be unwarranted. Cuthbertson et al.6 concluded that their study does not support routine screening for retinopathy because the retinal complications resolve while treatment is continued and patients are asymptomatic. Malik et al.36 suggest that regular screening for visually asymptomatic patients under treatment with interferon for HCV is unnecessary. Panetta and Gilani1 conclude that pretreatment and subsequent eye examinations while on treatment may not be necessary in asymptomatic patients even with hypertension and diabetes mellitus.

Other investigators support routine screening. Lim and Shin14 conclude that interferon-associated retinopathy is generally asymptomatic and usually reversible without ocular complications, but because of the rare chance of the development of severe visual complications, regular screening for patients receiving treatment is recommended. Multiple studies also conclude that patients who undergo combination therapy (interferon and ribavirin), particularly those with hypertension, should have periodic retinal examinations.3, 33, 39

Future therapy for chronic hepatitis C virus 

New prospects for therapy include the introduction of specifically targeted antiviral therapy for HCV, such as small molecule inhibitors of viral proteins.7 Two protease inhibitors, telaprevir and boceprevir, are currently undergoing phase III clinical trials.7, 48, 49 Inhibition of HCV protease may help to enhance antiviral immune pathways and decrease viral replication.7 Various HCV polymerase inhibitors are also being studied, and it is anticipated that small-molecule inhibitors will soon be part of standard anti-HCV treatment.7

Case discussion 

Our 53-year-old hepatitis C patient represents a fairly typical case of interferon-associated retinopathy, with the presentation of cotton wool spots and retinal hemorrhages, but without maculopathy or other serious complications. His retinopathy started sometime after 2 months of treatment but before his 4-month retinal check. The retinopathy persisted for several months but resolved before the completion of treatment. However, the patient was visually asymptomatic during his treatment period. Laboratory tests found that anemia, neutropenia, and thrombocytopenia developed in this patient during treatment, but the values were stable enough that he did not require treatment with hematopoietic/growth factors. This patient was motivated with his viral clearance results and continued with the medication despite losing weight and suffering from persistent and bothersome systemic side effects. Treatment was stopped prematurely after 27 weeks because of the development of suspected neoplastic lung disease (presumed to be unrelated to the HCV treatment). This patient will be more likely to show HCV relapse because of the discontinuation of the treatment before receiving the full 48 weeks of planned therapy.

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Conclusion 

We chose a more conservative approach while monitoring this patient, although a standard protocol for monitoring patients treated with interferon and ribavirin has not been agreed on at this time. Screening for pre-existing retinopathy before initiation of HCV treatment is recommended for all patients. Frequency of follow-up should be determined on a case-by-case basis, with consideration of more frequent monitoring for visually symptomatic patients and for patients with a history of diabetes or hypertension. Modification or premature withdrawal from treatment should be considered for patients who develop more serious ocular complications (such as optic nerve or macular involvement). Although this patient was visually asymptomatic and his retinopathy resolved during treatment, we chose to monitor him monthly because of the risk of serious (although rare) ocular complications.

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References 

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PII: S1529-1839(10)00315-5

doi:10.1016/j.optm.2010.04.094

Optometry - Journal of the American Optometric Association
Volume 81, Issue 11 , Pages 580-586, November 2010

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