Is Combination Therapy Interferon and Ribavirin in Patients with Chronic Hepatitis C Infection Toxic for Eyes?

Abstract

Background: Many side effects of combination therapy using pegylated interferon (IFN) and ribavirin for treatment of chronic hepatitis C virus (HCV) infection have been well described. Ocular complications are fairly common. Diabetes mellitus (DM) and systemic hypertension are possible suggested risk factors for development of these complications. Purpose: To determine the frequency of retinopathy and its risk factors in patients treated with combined pegylated IFN and ribavirin for chronic hepatitis C infection. Methods: Eligible 98 patients for HCV treatment with pegylated IFN a-2a, a-2b, and ribavirin between October 2011 and March 2012 were included. All patients underwent a baseline full ophthalmological examination, and any visual complaints during treatment prompted a repeat eye examination. Results: Out of the eligible 98 patients, 48 (48.78%) patients received pegylated IFN alpha-2a, and the other 50 (51.21%) patients were treated with pegylated IFN alpha-2b. Out of 98 patients, 21 (21.42%) had diabetes; 19 (19.38%) patients had hypertension and 16 (16.32%) patients had both diabetes; and hypertension. Only 8 patients (8.16%) had documented retinopathy [2 had DM; one had hypertension; 4 had both hypertension and diabetes; and one patient without DM or hypertension]. Univariate logistic regression analysis revealed that diabetic, hypertensive patients are at increased risk for development of IFN-associated retinopathy (IAR) (P=0.007, Odds ratio=6.5, 95% confidence interval=1.56–27. Conclusion: Retinopathy in chronic HCV-infected patients undergoing treatment with combination of pegylated IFN-alpha and ribavirin therapy appears to be relatively low, and treatment cessation is rarely needed. Diabetic, hypertensive patients are at increased risk for IAR and are recommended to be ophthalmologically followed-up.

Introduction

Hepatitis C virus (HCV) is a major cause of chronic liver disease with estimated 170 million people infected worldwide. The spectrum of severity of the liver disease associated with HCV varies widely from nonspecific, minimal inflammatory changes to cirrhosis and hepatocellular carcinoma.¹ The current standard treatment for chronic hepatitis C is the combination of pegylated interferon (IFN)-alpha and ribavirin.² There are 2 formulations of pegylated IFN available, IFN alpha-2a and pegylated IFN alpha-2b. They differ by virtue of the size and configuration of the polyethylene glycol molecules bound to the IFN molecule.^3,4

The side effect of combination therapy using standard IFN and ribavirin has been well described.^5–8 The major types of side effects include fatigue, influenza-like symptoms, gastrointestinal disturbances, neuropsychiatric symptoms, and hematologic abnormalities.^5,6 Visual changes are fairly common, but the exact incidence is unknown.⁹ The most commonly documented eye complications are cotton wool spots and retinal hemorrhages, but most IFN-related retinopathy is asymptomatic and reversible.

The aim of this study was to determine the frequency of ophthalmological complications in patients under combination of pegylated IFN and ribavirin-based treatment for chronic HCV and risk factors for development of these complications.

Methods

A total of 106 patients with histologically confirmed chronic hepatitis undergoing treatment for it were followed up at the Outpatient Clinic of Tropical Medicine Unit and Ophthalmic Center of the Mansoura University Hospital between October 2011 and March 2012. At the initial clinic visit, a full history (especially pre-existing eye diseases/symptoms) was taken, and physical examination was performed, and patients were evaluated for their treatment candidacy.

Laboratory tests, including a positive anti-HCV antibody by third-generation ELIZA, quantitative HCV viral RNA, a complete blood count, complete liver function tests, serum AFP, triglyceride, TSH, fasting and postprandial blood sugar, autoimmune panel (ANA), coagulation studies, and hepatitis B serology, were performed. A baseline ECG tracing was determined in all patients. Percutaneous liver biopsy (≥15 mm in length) was performed for all the patients. Liver biopsy specimens were reviewed by a single pathologist. For each liver biopsy specimen, hematoxylin and eosin and Masson's trichrome stains were available. Liver biopsy assessed by METAVIR score was determined in all cases.¹⁰

Inclusion criteria were adults (above 18 years) of both genders, HCV positive by PCR, and any stage of compensated HCV-related liver diseases that were histologically confirmed HCV-positive liver biopsy. Exclusion criteria were patients with any serological evidence of infection with other viruses (HBV and HIV); all other known causes of liver diseases were excluded on the basis of analytical, clinical, and epidemiological data: autoimmunity, metabolic and genetic disorders, NASH, alcohol intake, drug toxicity, and patients with decompensated cirrhosis and hepatocellular carcinoma.

Patients were treated with pegylated IFN alpha-2a or pegylated IFN alpha-2b. The dosage of pegylated IFN-alpha-2a was 180 mcg injected subcutaneously once weekly. Pegylated IFN-alpha-2b dosage was 1.5 mcg/Kg. All patients were treated in addition to pegylated IFN with ribavirin orally in divided doses at 1000 mg/d and 1200 mg/d in patients weighing <75 kg and >75 kg, respectively.

Patients were educated on potential complications, especially visual symptoms, and were assessed for safety, tolerance, and efficacy of therapy weekly for first month and then every month till the end of the treatment.

Ophthalmic examinations were carried out before the start of treatment and at 2, 4, 8, 12, and 24 weeks, and then every 3 month, after initiation of treatment until completion of therapy or until the retinopathy disappeared. Ocular examination consisted of best-corrected visual acuity, intraocular pressure measurement, baseline fundus examination, periodic fundus examination during the course of treatment, or at any time the patient complains of visual symptoms. Fundus for selected cases was photographed. The decision to stop therapy for ophthalmic complications was determined by the ophthalmologist. Other reasons unrelated to eye complications resulting in treatment cessation had included IFN, or ribavirin complications were determined by the internist. All patients provided written informed consent, and the Institutional Review Board (IRB) of our Faculty of Medicine approved this follow-up study.

Statistical analysis

SPSS (statistical package for social science) program version 10 was used for statistical analysis. The qualitative data were presented in the form of number and percentage. The quantitative data were presented in the form of mean, standard deviation, and range. Univariate and multivariate analysis of patient outcome risk ratios were performed using Cox's proportional hazard regression analyses. P-values<0.05 was considered significant.

Results

Initially, a total of 106 patients with chronic HCV infection under treatment with combined therapy with pegylated IFN and ribavirin from October 2011 to March 2012 were included in this study. Only 8 patients were excluded, as they neglected the ophthalmological follow-up. Thirty patients (30.61%) were nonresponders (17 at 12 weeks from starting the therapy and 13 patients at 24 weeks), but those patients with retinopathy among nonresponders continued in this study with regard to ocular examinations until the retinopathy resolved. Out of the initial 106 patients were in this study, 98 patients fulfilled the inclusion criteria and continued in this study, where 48 patients (48.97%) were under pegylated IFN-alpha-2a, while the other 50 patients (51.02%) under therapy with pegylated IFN-alpha-2b. Studied patients were [61 (62.2%) men and 37(37.7%) women], with a mean age of 43.4±10.9.

Distribution of patients and IFN-associated retinopathy (IAR) among studied groups are determined in Table 1. The mean duration of hypertension was 4.39±39 years, and the mean duration of diabetes mellitus (DM) was 5.25±35 years. Eleven (29.73%) patients were on insulin therapy, while 18 (48.64%) were on hypoglycemic drugs, and 8 (21.62%) patients were on combined insulin and oral hypoglycemic drugs.

Table 1.

Distribution of Patients and Interferon-Associated Retinopathy Among Studied Groups

Parameter	DM No. (%)	HTN No. (%)	DM+HTN No. (%)	Neither condition No. (%)
No. of patients (%)	21 (21.42%)	19 (19.38%)	16 (16.32%)	42 (42.85%)
Retinopathy (%)	2 (2.04%)	1 (1.02%)	4 (4.8%)	1 (1.04%)
Retinopathy%	25%	12.5%	50%	12.5%

No. number; HTN, hypertension; DM, diabetes mellitus.

Among 98 patients who continued this study (Table 2), 8 patients (8.16%) were found to have documented retinopathy of cotton wool spots; all patients were asymptomatic with preserved visual acuity, except one patient with diminished vision. The patients with documented retinopathy (Table 1) were 2 patients with DM only and 1 patient with hypertension only, 4 patients with combined DM and hypertension, and lastly one patient without DM or hypertension.

Table 2.

Characteristics of Patients with Retinopathy

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7	Case 8
Age (yr)	48	51	46	44	53	41	43	50
Gender	M	M	F	M	F	F	F	F
Liver biopsies (Metavir)	A3 F3	A1 F2	A2 F1	A3 F2	A1 F3	A2 F2	A3 F3	A2 F3
BRE	NL	NL	NL	NL	NL	NL	NL	NL
Onset of IAR	4 We	9 We	24 We	12 We	20 We	8 We	12We	9 We
HTN (Y/N)	Yes	Yes	No	No	yes	Yes	No	Yes
DM(Y/N)	Yes	No	No	Yes	Yes	Yes	yes	Yes
Plt.Count(×103/mm³⁾	153	168	148	95	118	156	230	210
WCC(×103/m³⁾	3.2	4.7	5.6	6.8	7.6	5.3	5.6	8.3
ALT (IU/L)	65	57	67	105	134	121	60	93
Hb (×g/dL)	13.2	14.5	12.6	15.1	13.6	14.3	13	13.5
Type of retinopathy	M.L.CWS	M.B.CWS	W.CWS	M.B.CWS	M.R.CWS	M.L.CWS	M.B.CWS	M.L.CWS
Tx management	Continues	Continues	Stopped	NR at 24w	NR at24w	NR at12w	Continues	NR at12w

BRE, Baseline retinal examination; NL, normal; We, week; IAR, interferon-associated retinopathy; Plt, platelets; WCC, white cell count; ALT, alanine aminotransferase; Hb, hemoglobin; CWS, cotton wool spots; W.CWS, worsening CWS; M, mild; L, left; R. right; B, both Tx, treatment; NR, nonresponder.

Logistic regression analysis of factors affecting retinopathy was also carried out. Combined DM and hypertension were found to be a factor for predicting retinopathy (Table 3).

Table 3.

Logistic Regression Analysis of Factors Associated with Retinopathy

Factor	Odds ratio	95% CI	P-value
Diabetes mellitus	1.25	0.27–5.94	0.68
Hypertension	0.57	0.09–3.88	0.61
Diabetes mellitus + hypertension	6.5	1.56–27.3	0.007^a
Neither diabetes mellitus nor hypertension	0.17	0.03–1.13	0.07

P<0.05, significant.

CI, 95% confidence interval.

The retinopathy was noted at the 4- to 24-week period after initiation of combined therapy and disappeared in 7/8 (77.5%) patients in a 4–8-week period. Interestingly, one patient developing vitreous hemorrhage resulting from retinal tears with retinal detachment, and vitrectomy was done after stoppage of therapy at 24 weeks, and this patient was not diabetic nor hypertensive; the other 7 patients with retinopathy; 3 patients continued the therapy till the end of treatment (48 weeks); 2 nonresponder patients at week 12; and the 2 nonresponders at 24 weeks, but under strict ophthalmologist observation until retinopathy resolved.

Discussion

IAR was first recognized in 1990 when Ikebe and associates reported a 39-year-old patient who developed retinal hemorrhages and cotton wool spots after intravenous administration of IFN.¹¹ The exact mechanism of retinopathy and subconjunctival hemorrhage in patients with chronic viral hepatitis receiving IFN therapy is unclear.¹² With IFN–ribavirin combination therapy, diabetes, hypertension, and response to treatment were considered as possible risk factors.^13,14 However, the results are not conclusive because of the small number of patients examined. The underlying mechanism of IAR is not completely understood. It is proposed that an immune complex deposition leading to cotton wool spot formation and occlusion of retinal capillaries. An ischemic insult, similar to that seen in hypertensive and diabetic patients, could be regarded as a potential mechanism. Disturbance in retinal microcirculation substantially augmented with a pre-existing arteriosclerosis favors the genesis of IFN-induced retinopathy.^13,15

In our study, we aimed to determine the prevalence of ocular complications and its risk factors among patients with chronic HCV infection under treatment with combination therapy and if these complications need discontinuation of therapy or not.

Earlier studies reported a relatively high incidence of retinopathy ranging from 19% to 64% during treatment with IFN, most likely is the result of a smaller sample size in these study. Moreover, the included patients were treated with nonpegylated IFNs using much higher doses, with a high tissue concentration and possibly higher risk of IAR.^16,17

In this study, we found that ocular complications during treatment were reported from 8 (8.16%) patients only with documented retinopathy. Moreover, symptomatic retinopathy was even rare and was seen in one patient (1.02%), and treatment stoppage was only needed in this case. In each case, IAR resolved without long-term sequel, except one patient who had to prematurely terminate their treatment regimen due to associated IAR.

Moreover, the ocular side effects of ribavirin were not reported in our study. IAR developed by 12 weeks in most (6/8, 75%) of patients after the start of combination therapy and disappeared in the majority of the patients (7/8, 87.5%) during the following 4–8-week period. Most of our studied patients with IAR continued combined therapy without interruption. This suggests that treatment can be continued despite the development of retinopathy in many patients. Regarding the disease course, Okuse et al. supported our work with a similar results and suggested a benign uneventful course related to IAR.¹⁷

Okuse et al. reported a higher frequency of retinopathy associated with IFN–ribavirin combination therapy (19%) compared to our result (8.16%).¹⁷ A relatively small number of patients in Okuse study (73 patients) and higher daily dose of IFN therapy probably explains the observed differences.

Panetta and Gilani reported an overall low occurrence of IAR (3.8%), and symptomatic retinopathy is even rare (1.09%) in chronic HCV-infected patients treated with IFN and ribavirin compared with our results with different patients' characteristics, comorbid status, and HCV genotypes.¹⁸

Logistic regression analysis of factors affecting retinopathy did not indicate pretreatment of DM as predictive factors of IAR. On the other hand, other studies concluded that patients with DM are more susceptible to the development of retinopathy.^12,19 Panetta and Gilani agreed with our results stating that DM is not a risk factor for the development of IAR.¹⁸

In our study, logistic regression analysis excluded hypertension alone as a risk factor for the development of IAR. One other study agreed with us and suggested also that diabetes and hypertension are not risk factors for the development of such a retinopathy.¹⁸

On the other hand, Sharrett et al. assumed that chronic hypertension is associated with the thickening of the walls of the arteries and small arterioles.²⁰ Okuse et al. added that hypertension was a factor for predicting the development of IAR, and hypertensive retinopathy induces the formation of flame-shaped hemorrhages and white cotton wool spots, which are also seen in IAR. Hence, systemic hypertension and IAR may be closely related each other.¹⁷

In our study, logistic regression analysis concluded that diabetic, hypertensive patients are at risk for developing retinopathy when receiving IFN–ribavirin combination therapy for chronic HCV infection. Several researchers agreed with our data.^12,14,17 On the other hand, Panetta and Gilani reported that patients with hypertension and diabetes may not be at higher risk for IFN-induced retinopathy.¹⁸

In this study, vitreous hemorrhage is a rare, atypical finding in nondiabetic, nonhypertensive patients that necessitated vitrectomy and stoppage of therapy, and although it is rare and a typical eye complication of IFN therapy, it was reported before by Kado and coworkers with a similar presentation in a 61-year-old woman.²¹ A typical retinal and ocular side effects have also been reported with IFN, including branch retinal artery occlusion,²² retinal detachment,²³ optic disc edema, neovascular glaucoma, vitreous hemorrhage, and panophthalmitis.²⁴ Fortunately, none of these complications were reported in our case series.

In conclusion, our study suggests an overall low occurrence of retinopathy (8.16%) in chronic HCV-infected patients treated with combined therapy than with pegylated IFN. Diabetic, hypertensive patients are at increased risk for IAR. IFN therapy can be continued under ophthalmic follow-up, especially for those at risk, even in the presence of retinopathy.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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