Role OF OCT-A TO Detect Possible Retinal Vascular Complications of Sofosbuvir (Sovaldi) in Patients With Hepatitis C Virus Infection
Conditions: HCV Infection
Sponsor: Mohamed Saad

 
1 
Tuesday, 15 August, 2019 
Faculty of Medicine, Cairo University Postgraduate  Research Program 
Template  
1.  Proposed Study Title 
Role OF OCT-A  TO Detect Possible Retinal Vascular 
Complications of Sofosbuvir (Sovaldi) in Patients With Hepatitis C 
Virus Infection. 
Degree  :    M.Sc 
2.Candidate Name: 
Mohamed Saad Emam Ahmed . 
(M.B.B.Ch October 6th University) 
Date of Registration :January 2019 
a. Occupation : 
-Resident of ophthalmology at Giza Memorial Institute for Ophthalmic Research 
-Visitor  Resident of ophthalmology at Kasr Alainy medical school – Cairo university   
b. Full mailing address :15 Hussein Darwish Building ,  Kornish Elnil St. 
Hadayek Helwan  ,  
Cairo, The  Arab Repuplic of Egypt 
c. Phone number 
+201007654385 
f. E-mail addresses 
Mohamedsaad2032@gmail.com 
1. Investigators Contact Information  
a.   Principal Investigator 
 
Prof. Dr.Magda Salah    
professor of Ophthalmology 
Faculty of medicine,Cairo university 
c.  
Department name 
Ophthalmology 
e. 
Phone number 
+ 
g. 
E-mail addresses 
magdasalah@kasralainy.edu.eg 
b. 
Other Investigators 
Dr. Hany El Mekawey 
Assistant professor of Ophthalmology 

 
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Faculty of medicine,Cairo university 
Dr. Yomna Amr 
Lecturer 
of 
Ophthalmlogy  
Faculty of medicine, Cairo university 
2. Background and Rationale: 
- Egypt − as an example of developing countries − has the highest 
prevalence rate of hepatitis C virus (HCV) infection that is suggested to 
be ∼14% in comparison with 2% in the developed countries. Among the 
14% who carry the antibodies, there are ∼9% who have an active 
infection .(1) 
- In chronic hepatitis C, the age of the patients is one of the considerable 
factors and has a significant role in determining the process of cirrhosis 
progression side by side with alcohol consumption, as − if there is no 
suitable antiviral treatment − cirrhosis develops at a faster rate from age 
40 years onward than in young patients. So, on-time antiviral treatment is 
essential to reduce the risk of cirrhosis progression . (2) 
- In early 2014, the American Association for the Study of Liver Diseases 
and the Infectious Diseases Society of America published a 
recommendation for the management of hepatitis C. In this 
recommendation, Sofosbuvir (Sovaldi) and ribavirin, with or without 
pegylated interferon, formed a crucial part of all first-line treatments for 
HCV genotypes 1–6, and also contributed in some second-line treatments 
.(3) 
- Sofosbuvir (Sovaldi) is a nucleotide analogue that inhibits the RNA 
polymerase enzyme, which is a necessary factor needed in hepatitis C 
virus replication . 
- The recommended dose for Sofosbuvir (Sovaldi) is 400 mg/day. Dose 

 
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adjustment in renal or hepatic insufficiency is commonly unrequired . 
- Sofosbuvir (Sovaldi) with ribavirin and interferon − as a triple-therapy 
strategy −was impressively appearing to be ∼90% effective in those with 
genotype 1, 4, 5, or 6 diseases. Sofosbuvir (Sovaldi) with just ribavirin − 
as a dual-therapy strategy appearing to be 70–95% effective in types 2 
and 3 diseases . (4,5,6) 
-  It was reported that the Sofosbuvir (Sovaldi) treatment displays common 
side effects as chest pain, migraine, memory impairment, dyspnea, 
gastrointestinal reflux, alopecia, depression, muscle spasm and blurred 
vision  , Moreover vision loss seems to be a growing side effect of 
Sovaldi . (7) 
- In an experiment was held at  the anatomy department, faculty of 
medicine, Menoufia University and  Published at  March 16, 2017 , 
Twenty adult male albino rats were used, each of them is weighting 170-
200 
grams 
were 
used 
in 
this 
experiment. 
The animals were divided in two groups:  Group I (Control):  included 
ten rats were kept without any treatment, Group II (Sovaldi treated): 
included ten rats that received 400 mg of Sofosbuvir (Sovaldi); these 
tablets were dissolved in distilled water and given for rats orally by 
gastric tube in a dose of 4 mg/kg per day for 5 weeks. (8) 
 
Corneal examination of the control group showed normal histological 
structure. Corneal examination of Sovaldi treated group showed focal 
areas of desquamation and separation of the epithelium. Some areas 
showed loss of corneal epithelium with apparent decrease in thickness of 
the epithelium. Corneal stromal collagen bundles were separated by 
multiple wide spaces, indicating corneal edema and showed cellular 
infiltration.  

 
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Immunohistochemical 
assaying 
showed 
that 
Sovaldi 
treatment 
significantly down-regulated the expression of E-cadherin. (8) 
 
Examination of haematoxylin and eosin stained sections of the retina in 
the control group (group I) showed normal histological structure. The 
outer nuclear layer exhibited darkly stained nuclei whereas the inner 
nuclear layer and ganglion cell layer showed lightly stained vesicular 
nuclei. Sections of Sovaldi treated group showed denuded pigmented 
epithelium in the photoreceptor layer and fissures in the outer nuclear 
layer. Extravasated Red Blood Corpuscles (RBCs) were noted in the 
inner nuclear layer and ganglion cell layer. Vacuoles and wide clear areas 
were present around ganglion cells that showed irregular dark nuclei 
Sovaldi  treatment significantly up-regulated the expression of 
fibronectin immunostaining.(8) 
-  A case report was published at May 2016 demonstrated A 57-year-old-
male developed ocular inflammation and retinopathy four weeks after the 
administration of Sofosbuvir (Sovaldi) for a hepatitis C infection (vision 
of 20/40 and 20/50 in his right and left eyes, respectively. Anterior 
segment exam showed conjunctival injection, scattered, fine keratic 
precipitates, and 3+ cell and flare bilaterally. Dilated fundus exam 
revealed bilateral peripapillary cotton-wool spots) . The ophthalmic 
findings resolved with discontinuation of the drug (Eleven weeks after 
cessation of ribavirin and Sofosbuvir (Sovaldi), his vision was 20/20 and 
20/25 with a resolution of the uveitis and cotton-wool spot) . (9) 
-  Another case report was published at June 2017  ,reported  A 39-year-
old Caucasian man presented with complaints of painless, progressive 
vision loss in his left eye over 24 hours. Past medical history was 
significant for hepatitis C secondary to blood transfusion. He completed 

 
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a six month course of 90 mg/400 mg Sofosbuvir (Sovaldi))  daily and 
500 mg ribavirin twice daily three days prior to the onset of his visual 
symptoms.  
Visual acuity was 20/20 right eye and 20/30 left eye. His color vision 
appeared. A 3 + afferent pupillary defect was noted in left eye. Fundus 
exam of the right eye revealed a 0.1 cup to disc with a “disc at risk” 
appearance. Left eye was remarkable for 360° hemorrhagic swelling of 
the 
optic 
disc 
with 
engorged 
venules  
Initial labs were unremarkable with normal erythrocyte sedimentation 
rate and C-reactive protein (obtained because of the observed cotton 
wool spots). MRI brain/orbits and MR venography were unremarkable 
and showed no optic nerve enhancement or signs of demyelinating 
disease. Humphrey visual field examination was normal in the right eye 
and showed incomplete superior and inferior altitudinal defects in the left 
eye . Two months after cessation of treatment , central visual acuity, 
color vision, and perimetry were unchanged. Fundus exam showed 
resolution of left optic disc swelling with diffuse pallor. His overall 
health remained excellent  (10) 
- A study was performed on 300 eyes undergoing Sofosbuvir (Sovaldi) 
therapy with peginterferon and ribavirin and on 300 eyes undergoing 
treatment with only peginterferon and ribavirin. Patients were evaluated 
for dry eye subjectively (Ocular Surface Disease Index questionnaire) 
and objectively, Schirmer test, tear film breakup time, and conjunctival 
nucleus/cytoplasm 
ratio 
by 
impression 
cytology. 
it was noticed that that dryness significantly associated with sofosubuvir 
group (11) 
References: 
1. Cuadros DF, Branscum AJ, Miller FD, Abu‐Raddad LJ. Spatial 

 
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epidemiology of hepatitis C virus infection in Egypt: analyses and 
implications. Hepatology 2014; 60:1150–1159.   
 2.Sarrazin C, Berg T, Ross RS, Schirmacher P, Wedemeyer H, Neumann 
U, Peck-Radosavljevic M. Prophylaxis, diagnosis and therapy of hepatitis 
C virus (HCV) infection: the German guidelines on the management of 
HCV infection. Z Gastroenterol 2010; 48:289.    
3. Hepatitis C Guidance: AASLD-IDSA Recommendations for Testing, 
Managing, and Treating Adults Infected with Hepatitis C Virus.” 
Hepatology 62, no. 3 (August 4, 2015): 932–954.  
4. Fung A, Jin Z, Dyatkina N, Wang G, Beigelman L, Deval J. Efficiency of 
incorporation and chain termination determines the inhibition potency of 2′-
modified nucleotide analogs against hepatitis C virus polymerase. 
Antimicrob Agents Chemother 2014; 58:3636–3645.   
5. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, 
Gordon SC, Jacobson IM. Sofosbuvir (Sovaldi) for previously untreated 
chronic hepatitis C infection. N Engl J Med 2013; 368:1878–1887.   
6. De Clercq E. Dancing with chemical formulae of antivirals: a panoramic 
view (part 2). Biochem Pharmacol 2013; 86:1397–1410.   
7. “Food and Drug Administration (FDA). Encyclopedia of 
Immunotoxicology (June 23, 2015): 333–333. 
8. El-Sherif NM. Histological and Immunohistochemical Studies on the 
Cornea and Retina of Sofosbuvir Treated Rats. Austin Journal of Anatomy. 
2017 March 16 4(2):1068. 
 9. Chin-Loy K, Galaydh F, Shaikh S. Retinopathy and uveitis associated 
with sofosbuvir therapy for chronic hepatitis C infection. Cureus. 2016 
May;8(5): e597. 

 
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10. Manoharan N, Subramanian PS. A case of non-arteritic anterior ischemic 
optic neuropathy after completion of Harvoni therapy. American journal of 
ophthalmology case reports. 2017 Jun 1;6:55-57. 
11. Salman AG. Ocular surface changes with Sofosbuvir in Egyptian patients 
with hepatitis C virus infection. Cornea. 2016 Mar 1;35(3):323-328. 
12. Myers JP, Di Bisceglie AM, Mann ES. Cryoglobulinemia associated with 
Purtscher-like retinopathy. American journal of ophthalmology. 2001 Jun 
1;131(6):802-804. 
13. Chebil A, Mammouri R, Abdallah MB, El Matri L. Purtscher-like 
retinopathy as a rare presentation of cryoglobulinemia. Middle East African 
journal of ophthalmology. 2016 Apr;23(2):219. 
11. Objectives: 
The purpose of this study is to prospectively evaluate the  value of 
Optical coherence tomography angiography (OCT-A) for the of detection of  
suspected retinal complications With Sofosbuvir (Sovaldi) in Patients With 
Hepatitis C Virus Infection. 
12. Study Design  :  
Descriptive prospective cohort study (pilot study)  
13. Study Methods  
During 3 months duration ( the treatment course duration) , Optical 
coherence tomography angiography (OCT-A) will be performed to 30 eyes of 
30 patients with a documented diagnosis of chronic hepatitis C before and after 
receiving dual-therapy planning (Daclatasvir − Sofosbuvir (Sovaldi)).  . 
All OCT-A examinations will be performed at the Ophthalmology 
Department, Faculty of Medicine, Cairo University. 

 
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Inclusion criteria: 
- Age between 20 and 80 years. 
- Patients with chronic hepatitis C enrolled for (Daclatasvir – Sofosbuvir 
(Sovaldi)) .  
- Patients who have normal ocular and fundoscopic examination before the 
onset of treatment.  
Exclusion criteria: 
 Relapsed cases who have formerly taken the antiviral therapy (depending 
on the basis of medical record and filing system), or treated with 
interferon for any other cause . 
 Patients with elevated renal functions or positive Rheumatoid factor (as a 
clue to diagnose Purtscher like retinopathy which is  a rare presentation 
of cryoglobuinemia , considered one of extra hepatic manifestations of 
HCV )  
Methodology in details: 
 the patients with a documented diagnosis of chronic hepatitis C , normal 
renal functions And Rheumatoid factor tests (to exclude Purtscher like 
retinopathy  as a rare presentation of cryoglobuinemia which considered 
one of extra hepatic manifestations of HCV)  will  undergo a 
comprehensive ophthalmic examination including: 
               • Manifest refraction  
• Corrected distance visual acuity 
• Anterior segment examination using slit lamp  and tear film 
breakup time test  
               • Fundus examination  

 
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 Recent OCT-A will be performed to all patients before Treatment 
Administration. 
 Examination will be performed using Optovue AngioVue® (Optovue, 
Inc., Freemont, CA), which uses split-spectrum amplitude-decorrelation 
angiography algorithm, which minimizes motion noise. This system also 
allows quantitative analysis, since it provides numerical data about flow 
area and flow density maps. 
 The patient will be examined before and after finishing the treatment 
course  
 OCT-A image acquisition 
OCT-A will be done for all patients who are instructed to focus on a fixation 
target. OCTA images are obtained using the RTVue XR Avanti (AngioVue; 
Optovue Inc, Fremont, California, USA) machine and the incorporated 
AngioVue OCT-A system. Algorithm used is Split-Spectrum Amplitude 
Decorrelation Algorithm (SSADA). The scans which will be included in the 
study are of high signal strength more than 0.7 and they will be carefully 
inspected for motion artifacts. Automatic segmentation of intraretinal layers 
will be done using the automated software of the machine (version 2016.2.0; 
Optovue Inc). Angio-retina scan sizes in this study will be 6 X 6 mm for all 
eyes. Assessment of the macular vessel density will be done for superficial 
vascular layer, capillary plexus, deep capillary plexus and all retinal plexuses). 
Assessment of the foveal avascular zone on both superficial vascular layer 
(SVL) and deep capillary plexuses DCP; including its size, perimeter and 
circularity (regularity) index. Circularity index is a measure of compactness of 
a shape relative to a circle. The circularity index of a circle is 1.0. Thus, a ratio 
closer to 0 indicates an irregular shape, and that closer to 1.0 indicates a 
circular shape. 

 
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All results will be in numerical values (percentage) to compare retinal 
vascularity before and after using the drug. Best corrected visual acuity (in 
values from o.o5 to 1.0) , dryness (in seconds) will be also measured before 
and after drug administration and it will be compared .                      
Possible Risk: 
As a fast, safe and noninvasive procedure to assess the chorioretinal 
microvasculature, OCT-A has been increasingly used in retinal diseases  
Primary outcomes: 
- Evaluate the suspected retinal vascular complications With Sofosbuvir 
(Sovaldi) ) in Patients With Hepatitis C Virus Infection, All results will be in 
numerical values (percentage) to compare retinal vascularity before and after 
using the drug..  
- Comparing best corrected visual acuity  (in values from o.o5 to 1.0) before 
and after drug administration . 
Secondary outcome parameters (other outcomes to be assessed): 
- 
Measuring amount of ocular dryness using Tear-up breaking test and 
Schirmer's test , dryness will be evaluated in seconds before and after 
drug administration and it will be compared .                        
- Confirm the advantages of OCT – A  Detection retinopathy 
- Assist in assessment of late ocular complications with  Sofosbuvir 
(Sovaldi) in Patients With Hepatitis C Virus Infection (the research 
can be used as a guide for further researches) .. 
 
Sample size (number of participants included): 
Convenience sample   
30 eyes of 30 patients with a documented diagnosis of chronic hepatitis C  

 
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Statistical analysis plan: 
 Data management and analysis will performed using Statistical Package for 
Social Sciences (SPSS). Median and range for non-parametric measures and 
ordinal (scores) data. Numerical data will be presented as means ± standard 
deviations (SD). Categorical data will be presented as number and percentages 
%. Pairwise comparisons between the two groups for normally distributed 
variables will be done using the Student’s t-test; the Mann–Whitney test, a 
nonparametric test equivalent to the t-test, will be used in non-normally 
distributed variables. The Repeated measures ANOVA test will be used to 
compare the effect change within and between the study groups at different 
visits. The chi-square test or the Fisher’s exact test will be used to compare 
between the groups with respect to categorical data. All p-values will be two-
sided. 
P-values 
< 
0.05 
will 
be 
considered 
significant. 
Source of funding:  
No source of funding. 
9.Cooperation with other departments: 
10 Time Plan 
Expected Finish date: after collecting and analyzing data ( six months)