The number of chronically infected persons with the hepatitis C virus (HCV) worldwide is estimated to be 130 million to 170 million people.1 HCV is a major cause of morbidity, especially in the Western world and in some African countries, including Egypt.2 Egypt has the highest prevalence of HCV worldwide, with 14.7 % of its population estimated to have the disease.3
Combined pegylated interferon alpha (PEG IFN-α) and ribavirin therapy was the standard HCV treatment for many years,4 but this regimen has a relatively long duration and is often associated with harmful effects such as influenza-like illnesses, myalgias, depression, and cytopenias that are intolerable to some patients, resulting in premature treatment cessation and patient incompliance.5
For this reason, there was a shift in HCV treatment from PEG INF-α and ribavirin to sofosbuvir and ribavirin. Patients with HCV with the interferon-free, sofosbuvir-based treatment regimen had lower treatment discontinuation rates and better health-related quality of life.6
To our knowledge, no previous studies discuss the ocular (especially retinal) complications of sofosbuvir. Therefore, we investigated the anatomical and functional retinal complications of sofosbuvir during and after therapy.
Patients and Methods
This prospective, observational study was carried out from November 2015 to September 2017 in patients with chronic HCV infection. Patients received the same regimen of combined sofosbuvir and ribavirin therapy for 6 months. All cases were recruited from the National Liver Institute at Menoufia University (one of the viral hepatitis treatment centers of the national committee). Examination and follow-up of the cases were performed in the outpatient clinic of the Ophthalmology Department at Menoufia University. Exclusion criteria were: 1) any systemic disease that may be complicated by retinopathy, such as diabetes mellitus, hypertension, and autoimmune diseases; 2) patients previously treated with interferons (to exclude interferon retinopathy); and 3) any pathology that may interfere with optical coherence tomography (OCT) examinations such as dense cataracts, corneal opacity, and high myopia.
All included patients underwent best-corrected visual acuity (BCVA) assessments using logMAR units, anterior segment examinations using slit-lamps, intraocular pressure evaluation using a Goldmann applanation tonometer, and posterior segment examinations using slit-lamp biomicroscopy with +90 diopters (D) and +78 D Volk lenses (Volk Optical, Mentor, OH). Fundus fluorescein angiography (FFA) was used to detect retinal ischemia or macular edema, OCT was employed to detect retinal nerve fiber layer (RNFL) thickness and central macular thickness (CMT); and electroretinogram (ERG) tests were utilized to detect rod and cone functions. All examinations were implemented before and after treatment completion. Follow-up by ophthalmic examination was completed every month during treatment and then every 3 months for 6 months after treatment completion.
All included patients received complete information about the study and provided written informed consent. This study was approved by the clinical research committee of the Menoufia University Hospital and it followed the tenets of the Declaration of Helsinki.
All data were expressed as mean ± standard deviation. Analyses were achieved using SPSS version 16 (SPSS, Chicago, IL). P values of less than .05 were regarded as statistically significant.
The number of patients infected with HCV is increasing worldwide; more than 20,000 new cases emerge every year. HCV infections frequently persist and are the leading causes of chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation in Egypt.3,7
Treating HCV infections has evolved, especially during the past decade. The goal of treatment is to prevent HCV complications by eliminating the virus. Interferon PEG IFN-α and ribavirin combination was the standard treatment for HCV in Egypt for many years, but this regimen was associated with a wide number of adverse effects; fever, headache, fatigue, and myalgias are common in most of patients, especially coinciding with the initial injections.
There are some adverse events that may require dose modification or can lead to the discontinuation of therapy, such as depression and irritability. Pancytopenia, characterized by (decreased granulocytes, platelets, and red blood cell counts) may occur during treatment; decreases are usually mild, although they can be dose limiting if cell counts are initially low. Interferons can induce autoimmune phenomena, the most frequent being autoimmune thyroiditis with either hypothyroidism or hyperthyroidism. Severe or life-threatening side effects of interferons occur in 0.1% to 1% of patients; these effects include thyroid, visual, auditory, renal, and cardiac impairments, as well as pulmonary interstitial fibrosis. Unfortunately, some of these side effects may be irreversible.8
There are a wide range of ocular complications caused by alpha interferons. The most common manifestations of interferon-related ocular toxicity is retinopathy, especially retinal hemorrhage and/or cotton-wool spots.9 Other atypical interferon-inducing ocular complications have been reported, such as optic disc edema, macular edema, periphlebitis, oculomotor nerve palsies, neovascular glaucoma, preretinal hemorrhage, subconjunctival hemorrhage, vitreous hemorrhage, retinal vein occlusions, and panophthalmitis.10
The above-mentioned adverse effects, in addition to patient incompliance, resulted in a shift in treatment regimen from the interferon-ribavirin to the sofosbuvir-ribavirin combination.
The aim of this study was to search for the anatomical and functional retinal complications of sofosbuvir during and after therapy. Our study revealed that there were no signs of retinopathy or optic nerve affection with sofosbuvir use, indicating that this treatment regimen may have less-severe side effects than current treatments. Sofosbuvir is a HCV-specific uridine nucleotide NS5B polymerase inhibitor with potent pan-genotypic activity. It is a well-tolerated drug with safety profiles more favorable than the interferon-ribavirin combination,11 and it is recommended to be given in combination with ribavirin rather than ribavirin alone.12
Other reports provide further insights into potential side effects of sofosbuvir. For example, Chin-Loy et al. described a case report of a 57-year-old-man who developed ocular inflammation (conjunctival injection, scattered, fine keratic precipitates, and 3+ cell and flare bilaterally) and retinopathy (bilateral peripapillary cotton-wool spots) 4 weeks after sofosbuvir and ribavirin administration for HCV infection. Hearing loss, rheumatologic disease, and essential tremor were also noted. The authors did not confirm if these findings were related to treatment or to HCV infection-induced autoimmune processes with associated seroconversion of various indexes of autoimmunity, including rheumatoid factor (RF) and antinuclear antibody (ANA) (as the patient was RF- and ANA-positive). Eleven weeks after cessation of ribavirin and sofosbuvir, his vision was 20/20 and 20/25 in the right and left eyes, respectively; ocular inflammation and cotton-wool spots were resolved after prednisolone acetate use.13
Additionally, a prospective, randomized, comparative study was performed by Salman14 on 300 eyes undergoing sofosbuvir therapy with peginterferon and ribavirin and on 300 eyes undergoing treatment with only peginterferon and ribavirin. Patients were evaluated for dry eye subjectively with an Ocular Surface Disease Index questionnaire and objectively via Schirmer tests, tear film breakup time, and conjunctival nucleus / cytoplasm ratio by impression cytology. Salman stated that tear function impairment and squamous metaplastic changes in the ocular surface occurred in patients with chronic HCV treated with sofosbuvir combined with other antivirals.
In this study, we discussed only the retinal complications of combined sofosbuvir and ribavirin treatment and did not provide insights into the anterior segment complications such as dry eye because dry eye is a very common disease in Egypt and it has many other causes such as trachoma, which is endemic in Egypt; therefore, there may be a conflict if dry eye was really related to sofosbuvir or to any other cause.
Limitations of this study are that we discuss the retinal complications of combined sofosbuvir and ribavirin treatment and not sofosbuvir alone. However, sofosbuvir cannot be given alone and must be given with ribavirin; therefore, it is not possible to analyze the effects of sofosbuvir alone. Also, FFA, OCT, and ERG examinations were performed without any signs of retinal or optic nerve affection.