|Year : 2019 | Volume
| Issue : 4 | Page : 161-165
Incidence of retinopathy in patients with chronic hepatitis C treated with dual and triple antiviral protocols
Mouaz A Abd-Elhadi1, Hazem E Haroun2, Noha M Khalil3, Safaa A Aboud2
1 Department of Ophthalmology, Ahmed Maher Teaching Hospital, Cairo, Egypt
2 Department of Ophthalmology, Faculty of Medicine, Beni Suef University, Beni Suef, Egypt
3 Department of Ophthalmology, Faculty of Medicine, Cairo University, Giza, Egypt
|Date of Submission||26-Mar-2019|
|Date of Acceptance||26-Jul-2019|
|Date of Web Publication||17-Dec-2019|
MD Noha M Khalil
10 Street Haroun, Dokki, Cairo 12311
Source of Support: None, Conflict of Interest: None
Purpose The aim of this study was to compare the incidence of ophthalmological complications in chronic hepatitis C virus patients treated with dual versus triple antiviral protocols.
Study design A Prospective, observational, comparative study.
Setting Ahmed Maher Teaching Hospital and revised in the Outpatient Clinic of Ophthalmology Department of Beni Suef University.
Patients and methods One hundred and fifty chronic hepatitis C virus patients were treated by dual therapy of sofosbuvir and ribavirin for 6 months (group A), and 150 patients were treated by triple therapy of sofosbuvir, ribavirin, and interferon pegylated interferon (pegINF-α) for 3 months (group B). Full general and ophthalmological examinations were done at the baseline visit before receiving treatment and at 3 and 6 months after treatment. Any ophthalmological complications including deterioration in best corrected visual acuity, anterior segment inflammation, or retinal complications in the form of hemorrhages, soft exudates, or changes in cup/disk ratio were recorded.
Results In 11% of the patients under triple therapy, retinal hemorrhages and soft exudates were detected by the second visit; however, they resolved by the third visit. Patients under dual therapy showed no ophthalmological complications throughout the 6-month follow-up period. No uveitis or changes in best corrected visual acuity and cup/disk ratio were detected.
Conclusion Interferon-free protocols showed no retinal complications. However, the retinal complications related to the interferon-containing protocols resolved shortly within weeks. Thus, interferon-free protocols showed higher safety on the eye.
Keywords: hepatitis C virus, pegINF, retinal hemorrhages, ribavirin, sofosbuvir, soft exudates
|How to cite this article:|
Abd-Elhadi MA, Haroun HE, Khalil NM, Aboud SA. Incidence of retinopathy in patients with chronic hepatitis C treated with dual and triple antiviral protocols. Delta J Ophthalmol 2019;20:161-5
|How to cite this URL:|
Abd-Elhadi MA, Haroun HE, Khalil NM, Aboud SA. Incidence of retinopathy in patients with chronic hepatitis C treated with dual and triple antiviral protocols. Delta J Ophthalmol [serial online] 2019 [cited 2020 Apr 5];20:161-5. Available from: http://www.djo.eg.net/text.asp?2019/20/4/161/273320
| Introduction|| |
Hepatitis C virus (HCV) is considered an endemic raising public health concern in Egypt. According to the Egyptian Demographic Health Survey in 2008, the incidence of HCV infection in the Egyptian population has been 14.7%, with an annual seroconversion rate of 1000 . In 2013, an estimate of 7.3% HCV prevalence was suggested .
Interferon treatment stayed for a long time as the treatment of choice for HCV-infected patients. However, many side effects, mainly affecting the retina, have been linked to antiviral medications used for chronic HCV treatment, mainly interferon. Therefore, the recent protocols switched to interferon-free ones which aim to inhibit RNA replication leading to viral eradication without affecting the retina ,.
Sofosbuvir and ribavirin with and without interferon pegylated interferon (pegINF-α) (dual and triple protocols) have shown a sustained virological response in high rates and have been widely recommended .
Typical retinal complications are cotton wool spots and peripapillary retinal hemorrhages. Cotton wool spots can occur alone or combined with retinal hemorrhages. Retinal hemorrhages usually take linear and patchy distribution and may develop unilaterally or bilaterally ,,.
The aim of this study was to investigate the safety of different antiviral protocols used for chronic HCV treatment through monitoring retinal complications associated with dual and triple therapies prescribed to HCV-infected patients, throughout a 6-month follow-up period.
| Patients and methods|| |
In this prospective study, a total of 300 patients, admitted to Ahmed Maher Teaching Hospital in 2016 to receive anti-HCV treatment, were followed up throughout a 6-month period. Full ophthalmological examination was carried out in the Outpatient Clinic of the Ophthalmology Department of Beni Suef University. One hundred and fifty patients received dual therapy of sofosbuvir (Sovaldi; Gilead Science Inc., Foster City, California, USA) and ribavirin (Ribazole; Adwia, El Obor City, Cairo, Egypt) (group A) and 150 patients received triple therapy of sofosbuvir, ribavirin, and pegINF-α (Reiferon Retard; MINAPHARM, Heliopolis, Cairo, Egypt) (group B).
Group A received anti-HCV treatment in the form of sofosbuvir (400 mg tablets) and ribavirin (standard weight-based dose) orally for 6 months whereas group B received sofosbuvir (400 mg tablets) and ribavirin (weight-based dose) orally and pegINF-α (180 μg/week) in the form of weekly subcutaneous injections for 3 months.
Inclusion criteria were HCV-infected patients showing HCV positive serology with age ranging from 20 to 60 years. Chronic HCV was diagnosed by blood test with qualitative reverse-transcription polymerase chain reaction (RT-PCR; Amplicor HCV; Roche Diagnostics, 9115 Hague Rd, Indianapolis, USA) and was confirmed histologically by liver biopsy. Patients with retinopathy or ocular opacity at the baseline visit (first visit before starting treatment) or those with a history of diabetes, hypertension, or any autoimmune diseases affecting the retina were excluded from the study. In addition, patients prescribed to interferon for any medical reason other than HCV as well as patients showing liver cirrhosis or tumors of the liver by abdominal ultrasonography were also excluded from the study.
The sample size was calculated using Epi-Info version 7 Stat Calc (Centers for Disease Control and Prevension (CDC) in Atlanta, Georgia (US), WHO), based on the following criteria: complications rate of 10%, confidence level of 90%, and margin of error of 5%.
A case report form for every patient was designed. The form included cells for name, age, sex, and medical records (diabetes, hypertension, or autoimmune diseases). All patients were subjected to the following ophthalmological assessment during the baseline visit, the second visit (3 months later), and the final visit (6 months after the baseline visit): automated refraction, best corrected visual acuity expressed as decimal number, slit-lamp examination of the anterior segment of the eye, and fundus examination using indirect ophthalmoscopy. Further investigations in the form of colored fundus photographs and fundus flourescein angiography (FFA) were carried out in patients showing retinal changes in the form of retinal hemorrhages and/or cotton wool spots.
The study was approved by the Research Ethics Committee of the Faculty of Medicine, Beni Suef University. Data collection conformed to all local laws and was compliant with the principles of the Declaration of Helsinki. The selected patients were informed of the purpose of the study and its consequences with confirmation about the confidentiality of data and a written informed consent was signed by the selected patients.
Data were analyzed using the software statistical package for the social sciences [predictive analytics software (PASW) statistics for Windows, version 18.0; SPSS Inc., Chicago, Illinois, USA]. Frequency distribution as percentage and descriptive statistics in the form of mean and SD were calculated. χ2-Test, t-test, and correlations were done whenever needed. P values less than 0.05 were considered significant.
| Results|| |
The mean age of the patients in group A was 46.2±8.4 years and in group B was 45.5±8.2 years, with no statistically significant difference between both groups (P>0.05). In group A, 55.3% of the patients were men and 44.7% were women and in group B, 61.3% were men and 38.7% were women (P>0.05).
[Table 1] shows the incidence, the type, and the outcome of retinal complications as well as their statistical significance in both groups. [Figure 1] shows the distribution of retinal complications in group B.
|Figure 1 Distribution of complications in group B during the second visit.|
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Similarly, both groups showed no angiographic findings during the first visit. However, during the second visit, 33 (11%) eyes in group B showed areas of hypofluorescence in FFA corresponding to the hemorrhages and soft exudates seen clinically ([Figure 2]), whereas FFA of the eyes in group A showed no angiographic findings (P<0.001). By the third visit, the angiographic findings detected in the 33 eyes in group B resolved after discontinuation of the treatment after 3 months and eyes in group A remained free of angiographic findings (P>0.05).
|Figure 2 Colored fundus and fundus fluorescein angiography images for a case after triple therapy. The figure shows a patient with peripapillary and mid-peripheral cotton wool spots and mid-peripheral hemorrhages (arrows) (around upper and lower temporal arcades) at 3 months and complete disappearance of these findings at 6 months after starting triple therapy.|
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Throughout the three visits, best corrected visual acuity and cup/disk ratio remained unchanged with no statistically significant differences between both groups (P>0.05). Also, no anterior segment changes or signs of uveitis were detected in both groups during the three visits.
| Discussion|| |
Retinal hemorrhages and cotton wool spots are well-recognized side effects of antiviral therapy given to chronically infected HCV patients. They usually result from the presumed retinal ischemia caused by the given antiviral drugs, particularly interferon . Direct-acting antivirals are a new class of therapeutics that target-specific stages of HCV replication, thus reducing ophthalmic complications. Sofosbuvir, a newly introduced anti-HCV drug, is an oral nucleotide analog inhibitor of HCV nonstructural 5B polymerase, which acts as a chain terminator when incorporated into HCV-RNA, thus specifically targeting HCV without causing retinal damage . However, Chin-loy et al.  recently reported signs of retinopathy and uveitis in one patient receiving sofosbuvir. The 57-year-old male patient, reported in their study, who developed these complications showed also auditory loss, rheumatologic disorders, and tremors. The resolution of the ophthalmological complications following discontinuation of sofosbuvir raised more concerns about the safety of interferon-free protocols. However, it was a single case reported retrospectively. Furthermore, the relation of the development of retinopathy and uveitis to sofosbuvir intake alone was not conclusive as they pointed that these complications might be the result of autoimmune responses generated from the HCV itself.
In this study, both groups were subjected to sofosbuvir and ribavirin but pegINF-α was added to one group only (group B), despite the fact that 150 patients prescribed to the dual interferon-free protocol showed neither retinal complications nor signs of uveitis, 11% of patients’ eyes in group B showed retinal complications in the form of soft exudates (94% of retinal complications), and retinal hemorrhages (6% of retinal complications). However, these retinal complications resolved days to weeks later after cessation of treatment. Therefore, these complications could be attributed to the intake of pegINF-α.
Although the exact pathogenesis of retinopathy has not been described, it was suggested that leukocyte infiltration and immune-complex deposition in the retinal vessels would lead to ischemic episodes . Previous studies have concluded that the increase in plasma complement levels and plasma aggregation enhanced capillary infarction might be responsible for ischemic retinopathy ,.
In consistence with our findings, the incidence of pegINF-α attributed retinopathy has been widely reported in previous studies. In a systematic review, the incidence of retinopathy throughout the treatment period was estimated to be 27% . A prospective study reported 30% of retinopathy in 97 patients receiving pegINF-α . In another study, 34.4% of patients developed retinopathy in the form of cotton wool spots and retinal hemorrhages . Nevertheless, Panetta and Gilani  reported a low incidence of retinopathy (3.8%) in 183 chronically infected HCV patients treated with pegINF-α and ribavirin. However, this study adopted a retrospective design and included only symptomatizing patients which might have led to underreporting of the incidence of complications as nonsymptomatizing patients were not included in the study. This study also included diabetic and hypertensive patients which might constitute additional risk factors for the development of retinopathy. It is also worth pointing out that in this study, we excluded diabetic and hypertensive patients known to have a higher risk factor of developing interferon-related retinopathy ,, which might have led to this relatively lower incidence of retinal complications compared with other studies. However, all retinal complications diagnosed in our study resolved within days or weeks after discontinuation of treatment which link the retinal complications directly to the intake of pegINF-α and which agreed with other studies ,.
Furthermore, this study did not show any changes in the visual acuity of patients after dual or triple therapies, which might agree with other studies as well ,,,,.
| Conclusion|| |
Sofosbuvir is a safe drug showing no retinal complications, whereas pegINF-α may result in retinal complications in the form of soft exudates and retinal hemorrhages. However, these retinal complications are reversible. More studies with a larger sample size and longer follow-up period are recommended to investigate the safety of the newly emerging anti-HCV drugs to come up with the best and safest protocols to treat chronically infected HCV patients.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005; 5:558–567.
Waked I, Doss W, El-Sayed M. The current and future disease burden of chronic hepatitis C virus infection in Egypt. Arab J Gastroenterol 2014; 15:45–52.
Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC et al.
Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878–1887.
Jacobson I, Gordon S, Kowdley K, Yoshida EM, Rodriguez-Torres M, Sulkowski MS et al.
Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368:1867–1877.
European Association for Study of Liver. European Association for the Study of the Liver EASL clinical practice guidelines: management of hepatitis C virus infection. J Hepatol 2014; 63:392–420.
Fodor M, Nagy V, Berta A, Tornai I, Pfliegler G. Hepatitis C virus presumably associated bilateral consecutive anterior ischemic optic neuropathy. Eur J Ophthalmol 2008; 18:313–815.
Misiuk-Hojło M, Michałowska M, Banach I. Ocular manifestations during hepatitisC infection. Przegl Epidemiol 2007; 61:545–550.
Hayasaka S, Fujii M, Yamamoto Y, Noda S, Kurome H, Sasaki M. Retinopathy and subconjunctival haemorrhage in patients with chronic viral hepatitis receiving interferon alfa. Br J Ophthalmol 1995; 79:150–152.
Raza A, Mittal S, Sood GK. Interferon-associated retinopathy during the treatmentof chronic hepatitis C. J Viral Hepat 2013; 20:593–599.
Kaur H, Singh H, Grewal N, Kaur N. Sofosbuvir: a novel treatment option for chronic hepatitis C infection. J Pharmacol Pharmacother 2014; 5:278–284.
Chin-loy K, Galaydh F, Shaikh S. Correction: retinopathy and uveitis associated with sofosbuvir therapy for chronic hepatitis C infection. Cureus 2016; 8:3.
Guyer DR, Tiedeman J, Yannuzzi LA. Interferon-associated retinopathy. Arch Ophthalmol 1993; 111:350–356.
Sugano S, Suzuki T, Watanabe M. Retinal complications and plasma C5a levels during interferon alpha therapy for chronic hepatitis C. Am J Gastroenterol 1998; 93:2441–2444.
Sugano S, Yanagimoto M, Suzuki T. Retinal complications with elevated circulating plasma C5a associated with interferon-alpha therapy for chronic active hepatitis C. Am J Gastroenterol 1994; 89:2054–2056.
Vujosevic S, Tempesta D, Noventa F, Midena E, Sebastiani G. Pegylated interferon-associated retinopathy is frequent in hepatitis C virus patients with hypertension and justifies ophthalmologic screening. Hepatology 2012; 56:455–463.
Kim ET, Kim LH, Lee JI, Chin HS. Retinopathy in hepatitis C patients due to combination therapy with pegylated interferon and ribavirin. Jpn J Ophthalmol 2009; 53:598–602.
Panetta JD, Gilani N. Interferon-induced retinopathy and its risk in patients with diabetes and hypertension undergoing treatment for chronic hepatitis C virus infection. Aliment Pharmacol Ther 2009; 30:597–602.
Jain K, Lam WC, Waheeb S. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin. Br J Ophthalmol 2001; 85:1171–1173.
Nagaoka T, Sato E, Takahashi A, Yokohama S, Yoshida A. Retinal circulatory changes associated with interferon induced retinopathy in patients with hepatitis C. Invest Ophthalmol Vis Sci 2007; 48:368–375.
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.
Okuse C, Yotsuyanagi H, Nagase Y, Kobayashi Y, Yasuda K, Koike K et al.
Risk factors for retinopathy associated with interferon alpha-2b and ribavirin combination therapy in patients with chronic hepatitis C. World J Gastroenterol 2006; 12:3756–3759.
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.
[Figure 1], [Figure 2]