- Email: [email protected]
Low incidence of retinopathy during peginterferon α-2b and lamivudine therapy for chronic hepatitis B
Journal of Hepatology 45 (2006) 160–162 www.elsevier.com/locate/jhep
Letters to the Editor
Low incidence of retinopathy during peginterferon a-2b and lamivudine therapy for chronic hepatitis B To the Editor: With interest we read the paper by d’Alteroche et al. about ophthalmologic side-effects during interferon (IFN) therapy for viral hepatitis [1]. In this study retinopathy was found on fundoscopic examination in 24% of patients after IFN therapy, none of whom experienced ophthalmologic symptoms. Factors associated with an increased risk of developing retinopathy included a history of arterial hypertension, age above 45 years and treatment with pegylated a-interferon. Based on their findings, d’Alteroche et al. recommended regular fundoscopic examination for all IFN treated patients, particularly during the first months of treatment. We here present our experience on retinopathy in chronic hepatitis B-infected patients treated with peginterferon-a-2b (PEG-IFN). As part of a global randomized controlled trial we performed routine ophthalmological examination in PEG-IFN treated patients of our own center [2]. Twenty-eight HBeAg-positive chronic hepatitis B-infected patients were included in this study and randomized to PEG-IFN alone in a dosage of 100 lg per week or its combination with lamivudine (Table 1). Before and during treatment, corrected visual acuity testing and routine examination of the retina by indirect ophthalmoscopy and slit-lamp biomicroscopy were performed. None of the patients had ophthalmological symptoms or abnormalities on pre-treatment analysis. Ophthalmological examination during treatment was performed after a median treatment period of 14 weeks (range 5–33 weeks). During treatment, three patients complained of blurred vision, without clear underlying ophthalmological etiology. Overall, visual acuity did not decrease during PEG-IFN treatment compared to baseline (mean visual acuity 0.05 and 0.02 logMAR – logarithm of the minimum angle of resolution, respectively, p = 0.18). One of three patients with complaints of blurred vision showed retinal hemorrhage on fundoscopic examination, which resolved spontaneously within 5 weeks on continued therapy. No abnormalities were observed on fundoscopic examination in any of doi:10.1016/j.jhep.2006.04.003
the other patients during treatment. In all three patients with ophthalmologic symptoms, spontaneous recovery was observed during therapy without a need for dose adjustment. IFN associated abnormalities that can be found on fundoscopic examination include retinal hemorrhage, cotton wool spots, micro aneurysms, optic disc hyperemia and macular edema [3–5]. The reported incidence of retinopathy varies between studies, rates between 18% and 86% have been reported [4,5]. The observed incidence of retinopathy in our study was significantly lower compared to that observed by D’Alteroche et al. (4% vs. 24%, p = 0.01 by v2 test), and may be explained by multiple factors. First, we performed fundoscopic examination relative early during treatment (median 14 weeks). However, in other studies retinopathy was particularly observed within the first 3 months of treatment [1,4,5]. Second, in our study mean age was profoundly lower (34 ± 4.3 years), with only four patients (17%) aged 45 or above, which was found to be associated with an increased risk of retinopathy by d’Alteroche et al. Diabetes mellitus and arterial hypertension are other risk factors for developing retinopathy. In contrast to the study by d’Alteroche et al. none of our patients had a history of either risk factor. When excluding patients with hypertension and diabetes mellitus from analysis, our rate of retinopathy was still lower than found by D’Alteroche et al. (4% vs. 20%, p = 0.052 by Fisher’s Exact test). Correction for patient age was not possible with available data. Third, hepatitis C patients may be, irrespective of age and other risk factors, more at risk to develop retinopathy than hepatitis B patients. Retinopathy was found in 32% of untreated HCV patients, compared to 6% in non-HCV-infected controls [6]. A relation between retinopathy and type II cryoglobulinemia in HCV infection has been suggested [7,8]. The rate of retinopathy in our study was comparable to that in the subgroup of HBV patients in the study of D’Alteroche et al. HCV infection in combination with diabetes mellitus, arterial hypertension and higher age may thus predispose patients to develop retinopathy on IFN therapy.
Letters to the Editor / Journal of Hepatology 45 (2006) 160–162
161
Table 1 Clinical characteristics of peginterferon-a (and lamivudine) treated chronic hepatitis B patients Clinical characteristics at baseline (n = 28) Age Mean age 18–44 years 45 years or above Sex Male Biochemistry and virology Mean ALT Median HBV DNA Risk factors for developing retinopathy Arterial hypertension Diabetes mellitus
0/28 (0%) 0/28 (0%)
Antiviral treatment PEG-IFN + lamivudine PEG-IFN + placebo
14/28 (50%) 14/28 (50%)
Ophthalmologic examination Blurred vision Mean corrected visual acuity Retinopathy
Baseline 0/28 (0%) 0.05 logMAR 0/28 (0%)
*
34 ± 4.3 years (range 18–60 years) 24/28 (83%) 4/28 (17%) 20/28 (71%) 150 ± 33.5 U/l (range 47–394 U/l) 1.6 · 109 copies/ml (range 2.0 · 107–1.4 · 1010 copies/ml)
During treatment 3/28 (11%) 0.02 logMAR (p = 0.18)* 1/28 (4%)
Mean corrected visual acuity during peginterferon treatment compared to baseline testing by paired t test.
Despite the high frequency of retinopathy in many studies, symptomatic ocular adverse events are infrequently reported during IFN therapy (0.4% of patients) [1]. Although isolated cases of severe ophthalmologic complications have been reported, the observed abnormalities in IFN associated retinopathy are usually transient. Based on the transient character of PEG-IFN-related retinopathy, its association with other risk factors and the significantly lower incidence in hepatitis B-infected patients without these risk factors in our study, we question whether routine fundoscopic examination should be performed in this patient group. In our opinion, further studies should prove whether in hepatitis B-infected patients to be treated with PEG-IFN, fundoscopic examination should be performed in all patients. So far, we recommend to examine only those with an increased risk for developing retinopathy or in patients with known pre-existing retinopathy. References [1] d’Alteroche L, Majzoub S, Lecuyer AI, Delplace MP, Bacq Y. Ophthalmologic side effects during alpha-interferon therapy for viral hepatitis. J Hepatol 2006;44:56–61. [2] Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. Pegylated interferon alfa-2b alone or in
[3] [4] [5]
[6]
[7]
[8]
combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365:123–129. Tu KL, Bowyer J, Schofield K, Harding S. Severe interferon associated retinopathy. Br J Ophthalmol 2003;87:247–248. Hayasaka S, Nagaki Y, Matsumoto M, Sato S. Interferon associated retinopathy. Br J Ophthalmol 1998;82:323–325. Schulman JA, Liang C, Kooragayala LM, King J. Posterior segment complications in patients with hepatitis C treated with interferon and ribavirin. Ophthalmology 2003;110:437–442. Abe T, Nakajima A, Satoh N, Koizumi T, Sakuragi S, Ono T, et al. Clinical characteristics of hepatitis C virus-associated retinopathy. Jpn J Ophthalmol 1995;39:411–419. Abe T, Sakuragi S, Kuramitsu OT. Retinopathy associated with hepatitis C virus. Jpn J Clin Ophthalmol (Rinsho Ganka) 1993;47:297–300. Zegans ME, Anninger W, Chapman C, Gordon SR. Ocular manifestations of hepatitis C virus infection. Curr Opin Ophthalmol 2002;13:423–427.
Erik H.C.J. Buster 1, Martijn J. ter Borg 1, Johannes R. Vingerling 2, Harry L.A. Janssen 1 1 Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands 2 Department of Ophthalmology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands E-mail address: [email protected] (H.L.A. Janssen) doi: 10.1016/j.jhep.2006.04.003
Reply To the Editor: We appreciate the interest shown by Buster et al. in our paper concerning retinopathy lesions during interferon
(IFN) therapy for viral hepatitis [1]. They report cotton–wool spots in 1 out of 28 patients (4%) included in a multicenter prospective study comparing treatment with
Letters to the Editor
Low incidence of retinopathy during peginterferon a-2b and lamivudine therapy for chronic hepatitis B To the Editor: With interest we read the paper by d’Alteroche et al. about ophthalmologic side-effects during interferon (IFN) therapy for viral hepatitis [1]. In this study retinopathy was found on fundoscopic examination in 24% of patients after IFN therapy, none of whom experienced ophthalmologic symptoms. Factors associated with an increased risk of developing retinopathy included a history of arterial hypertension, age above 45 years and treatment with pegylated a-interferon. Based on their findings, d’Alteroche et al. recommended regular fundoscopic examination for all IFN treated patients, particularly during the first months of treatment. We here present our experience on retinopathy in chronic hepatitis B-infected patients treated with peginterferon-a-2b (PEG-IFN). As part of a global randomized controlled trial we performed routine ophthalmological examination in PEG-IFN treated patients of our own center [2]. Twenty-eight HBeAg-positive chronic hepatitis B-infected patients were included in this study and randomized to PEG-IFN alone in a dosage of 100 lg per week or its combination with lamivudine (Table 1). Before and during treatment, corrected visual acuity testing and routine examination of the retina by indirect ophthalmoscopy and slit-lamp biomicroscopy were performed. None of the patients had ophthalmological symptoms or abnormalities on pre-treatment analysis. Ophthalmological examination during treatment was performed after a median treatment period of 14 weeks (range 5–33 weeks). During treatment, three patients complained of blurred vision, without clear underlying ophthalmological etiology. Overall, visual acuity did not decrease during PEG-IFN treatment compared to baseline (mean visual acuity 0.05 and 0.02 logMAR – logarithm of the minimum angle of resolution, respectively, p = 0.18). One of three patients with complaints of blurred vision showed retinal hemorrhage on fundoscopic examination, which resolved spontaneously within 5 weeks on continued therapy. No abnormalities were observed on fundoscopic examination in any of doi:10.1016/j.jhep.2006.04.003
the other patients during treatment. In all three patients with ophthalmologic symptoms, spontaneous recovery was observed during therapy without a need for dose adjustment. IFN associated abnormalities that can be found on fundoscopic examination include retinal hemorrhage, cotton wool spots, micro aneurysms, optic disc hyperemia and macular edema [3–5]. The reported incidence of retinopathy varies between studies, rates between 18% and 86% have been reported [4,5]. The observed incidence of retinopathy in our study was significantly lower compared to that observed by D’Alteroche et al. (4% vs. 24%, p = 0.01 by v2 test), and may be explained by multiple factors. First, we performed fundoscopic examination relative early during treatment (median 14 weeks). However, in other studies retinopathy was particularly observed within the first 3 months of treatment [1,4,5]. Second, in our study mean age was profoundly lower (34 ± 4.3 years), with only four patients (17%) aged 45 or above, which was found to be associated with an increased risk of retinopathy by d’Alteroche et al. Diabetes mellitus and arterial hypertension are other risk factors for developing retinopathy. In contrast to the study by d’Alteroche et al. none of our patients had a history of either risk factor. When excluding patients with hypertension and diabetes mellitus from analysis, our rate of retinopathy was still lower than found by D’Alteroche et al. (4% vs. 20%, p = 0.052 by Fisher’s Exact test). Correction for patient age was not possible with available data. Third, hepatitis C patients may be, irrespective of age and other risk factors, more at risk to develop retinopathy than hepatitis B patients. Retinopathy was found in 32% of untreated HCV patients, compared to 6% in non-HCV-infected controls [6]. A relation between retinopathy and type II cryoglobulinemia in HCV infection has been suggested [7,8]. The rate of retinopathy in our study was comparable to that in the subgroup of HBV patients in the study of D’Alteroche et al. HCV infection in combination with diabetes mellitus, arterial hypertension and higher age may thus predispose patients to develop retinopathy on IFN therapy.
Letters to the Editor / Journal of Hepatology 45 (2006) 160–162
161
Table 1 Clinical characteristics of peginterferon-a (and lamivudine) treated chronic hepatitis B patients Clinical characteristics at baseline (n = 28) Age Mean age 18–44 years 45 years or above Sex Male Biochemistry and virology Mean ALT Median HBV DNA Risk factors for developing retinopathy Arterial hypertension Diabetes mellitus
0/28 (0%) 0/28 (0%)
Antiviral treatment PEG-IFN + lamivudine PEG-IFN + placebo
14/28 (50%) 14/28 (50%)
Ophthalmologic examination Blurred vision Mean corrected visual acuity Retinopathy
Baseline 0/28 (0%) 0.05 logMAR 0/28 (0%)
*
34 ± 4.3 years (range 18–60 years) 24/28 (83%) 4/28 (17%) 20/28 (71%) 150 ± 33.5 U/l (range 47–394 U/l) 1.6 · 109 copies/ml (range 2.0 · 107–1.4 · 1010 copies/ml)
During treatment 3/28 (11%) 0.02 logMAR (p = 0.18)* 1/28 (4%)
Mean corrected visual acuity during peginterferon treatment compared to baseline testing by paired t test.
Despite the high frequency of retinopathy in many studies, symptomatic ocular adverse events are infrequently reported during IFN therapy (0.4% of patients) [1]. Although isolated cases of severe ophthalmologic complications have been reported, the observed abnormalities in IFN associated retinopathy are usually transient. Based on the transient character of PEG-IFN-related retinopathy, its association with other risk factors and the significantly lower incidence in hepatitis B-infected patients without these risk factors in our study, we question whether routine fundoscopic examination should be performed in this patient group. In our opinion, further studies should prove whether in hepatitis B-infected patients to be treated with PEG-IFN, fundoscopic examination should be performed in all patients. So far, we recommend to examine only those with an increased risk for developing retinopathy or in patients with known pre-existing retinopathy. References [1] d’Alteroche L, Majzoub S, Lecuyer AI, Delplace MP, Bacq Y. Ophthalmologic side effects during alpha-interferon therapy for viral hepatitis. J Hepatol 2006;44:56–61. [2] Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. Pegylated interferon alfa-2b alone or in
[3] [4] [5]
[6]
[7]
[8]
combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365:123–129. Tu KL, Bowyer J, Schofield K, Harding S. Severe interferon associated retinopathy. Br J Ophthalmol 2003;87:247–248. Hayasaka S, Nagaki Y, Matsumoto M, Sato S. Interferon associated retinopathy. Br J Ophthalmol 1998;82:323–325. Schulman JA, Liang C, Kooragayala LM, King J. Posterior segment complications in patients with hepatitis C treated with interferon and ribavirin. Ophthalmology 2003;110:437–442. Abe T, Nakajima A, Satoh N, Koizumi T, Sakuragi S, Ono T, et al. Clinical characteristics of hepatitis C virus-associated retinopathy. Jpn J Ophthalmol 1995;39:411–419. Abe T, Sakuragi S, Kuramitsu OT. Retinopathy associated with hepatitis C virus. Jpn J Clin Ophthalmol (Rinsho Ganka) 1993;47:297–300. Zegans ME, Anninger W, Chapman C, Gordon SR. Ocular manifestations of hepatitis C virus infection. Curr Opin Ophthalmol 2002;13:423–427.
Erik H.C.J. Buster 1, Martijn J. ter Borg 1, Johannes R. Vingerling 2, Harry L.A. Janssen 1 1 Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands 2 Department of Ophthalmology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands E-mail address: [email protected] (H.L.A. Janssen) doi: 10.1016/j.jhep.2006.04.003
Reply To the Editor: We appreciate the interest shown by Buster et al. in our paper concerning retinopathy lesions during interferon
(IFN) therapy for viral hepatitis [1]. They report cotton–wool spots in 1 out of 28 patients (4%) included in a multicenter prospective study comparing treatment with