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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 111  |  Issue : 1  |  Page : 1-6

Ocular effects of hepatitis c virus antiviral drugs


1 Department of Ophthalmology, Ain Shams University, Cairo, Egypt
2 Department of Internal Medicine and Hepatogastroenterology, Ain Shams University, Cairo, Egypt
3 Department of Ophthalmology, Al-Mataria Teaching Hospital, Cairo, Egypt

Date of Web Publication26-Jul-2018

Correspondence Address:
Thanaa H Mohammed
Department of Ophthalmology, Ain Shams University, 11361 Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejos.ejos_14_18

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  Abstract 

Purpose The goal of this research is to find out the incidence of any ophthalmic adverse effects associated with sofosbuvir − ribavirin combination therapy in comparison with sofosbuvir − ribavirin − interferon combination therapy in patients having chronic hepatitis C.
Patients and methods A prospective nonrandomized comparative study was carried on 80 eyes of 40 patients with a documented diagnosis of chronic hepatitis C referred by the Internal Medicine and Hepatogastroenterology Department.
Study group 1 (20 patients; 40 eyes) patients enrolled in the dual-therapy delineation (a 24-week regimen of 400 mg/day sofosbuvir and a 600 mg/day ribavirin) and study group 2 (20 patients; 40 eyes) patients registered in the triple-therapy planning (12-week regimen of sofosbuvir and ribavirin plus 180-µg peginterferon α-2a subcutaneously weekly). All recorded patients were subjected to entire ophthalmic examination before the medicaments strategy inauguration with periodic examination at 3 and 6 months during the treatment plan using Schirmer test and tear film breakup time test.
Results Retinopathy has been evidenced at 3 months after treatment onset in 15% of group 2 candidates and receded at 6 months, which dates 3 months after treatment termination, with no cases of retinopathy in group 1 patients; the difference was statistically insignificant. Schirmer test and tear film breakup time results changed significantly over the 6-month study period. In study group 1, values of both tests decreased at 3 months after the start of sofosbuvir antiviral drug therapy and continued to dwindle throughout the period of follow-up. On the contrary, in study group 2, they decreased at 3 months after treatment onset but came to the common standard values 3 months after treatment discontinuation.
Conclusion In our research, both study groups show that the drug-induced dry eye effects were in any event reasonably mild and had trivial effect on one’s daily performance. The retinal lesions in our patients were peacefully asymptomatic, as there were no effects on the best corrected visual acuity (BCVA) in all patients throughout the 6-month study period.

Keywords: dry eye, hepatitis C, interferon, Schirmer test, sofosbuvir


How to cite this article:
Mohammed TH, Saad AH, Yosef TM, Lamee RG. Ocular effects of hepatitis c virus antiviral drugs. J Egypt Ophthalmol Soc 2018;111:1-6

How to cite this URL:
Mohammed TH, Saad AH, Yosef TM, Lamee RG. Ocular effects of hepatitis c virus antiviral drugs. J Egypt Ophthalmol Soc [serial online] 2018 [cited 2018 Aug 21];111:1-6. Available from: http://www.jeos.eg.net/text.asp?2018/111/1/1/237642


  Introduction Top


Egypt − as an example of developing countries − has the highest prevalence rate of hepatitis C virus (HCV) infection that is conjectured 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 jointly published a recommendation for the management of hepatitis C. In this recommendation, sofosbuvir 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 is a nucleotide analogue that inhibits the RNA polymerase enzyme, which is a necessary factor needed in hepatitis C virus replication [4].

The recommended dose for sofosbuvir is 400 mg/day. Dose adjustment in renal or hepatic insufficiency is commonly unrequired [5].

Sofosbuvir 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 with just ribavirin − as a dual-therapy strategy − was praiseworthy, appearing to be 70–95% effective in types 2 and 3 diseases [6].

Sofosbuvir as monotherapy for hepatitis C had scarcely been used, the same as ribavin [7].

Nagaoka and Yoshida [8] built their classification of the interferon (IFN)-induced retinopathy on the basis of disease seriousness into two essential groups: in the first one (mild retinopathy), the patients have fewer than four hemorrhages, cotton wool spots, or both throughout the treatment juncture, and in the second group (severe retinopathy), patients have more than five lesions.

Because ribavirin had scarcely been used as a monotherapy for the treatment of hepatitis C, its ramifications alone on retinopathy are alleged to be subtle. However, the incidence of retinopathy is higher in those who are treated for HCV (usually combination therapy of interferon and ribavirin) than those who are treated for hepatitis B (usually monotherapy of interferon), so ribavirin may be a suspicious offending factor in this increased incidence [9].

As sofosbuvir was merely incorporated into other drugs such as ribavirin and interferon in clinical safety trials, the unpropitious effects of just combinations have been judged. Common unfavorable effects are fatigue, headache, nausea, rash, and irritability. Most drawbacks are considerably more prevalent in interferon-containing regimens as compared with interferon-free ones. The addition of sofosbuvir to ribvirin and IFN is predominantly accompanied with more reduction in hemoglobin level and neutrophils [7].


  Aim Top


The goal of this research is to reveal the incidence of any ophthalmic adverse effects accompanied with sofosbuvir − ribavirin combination therapy in comparison with sofosbuvir − ribavirin − interferon combination therapy in patients having chronic hepatitis C.


  Patients and methods Top


A prospective nonrandomized comparative study was conducted on 80 eyes of 40 patients with a documented diagnosis of chronic hepatitis C referred by the Internal Medicine and Hepatogastroenterology Department.

Study group 1 (20 patients; 40 eyes) enrolled in the dual-therapy delineation and study group 2 (20 patients; 40 eyes) registered in the triple-therapy planning. All recorded patients succumbed to entire ophthalmic examination before the medicaments strategy inauguration with periodic examination of 3 and 6 months during the treatment plan including Schirmer test and tear film breakup time test.

Regarding the treatment protocol, a 24-week regimen of 400 mg/day sofosbuvir and a 600 mg/day ribavirin was initiated in 20 patients with HCV (group 1) versus 12-week regimen of sofosbuvir and ribavirin plus 180 µg peginterferon α-2a subcutaneously weekly in 20 patients with HCV (group 2).

Informed consents were secured from all patients, and the research had the approval of the Institutional Review Board and Ethics Committee of the Faculty of Medicine, Ain Shams University.

Inclusion criteria

The inclusion criteria included the following:
  1. Age between 20 and 60 years.
  2. Patients with chronic hepatitis C enrolled for triple therapy (INF − ribavirin − sofosbuvir) or dual therapy (ribavirin − sofosbuvir).
  3. Patients who have normal ocular and fundoscopic examination before the onset of treatment.


Exclusion criteria

The exclusion criteria were as follows:
  1. Diabetic and/or hypertensive patients.
  2. Patients with ocular media opacity.
  3. Relapsed cases who have formerly taken the antiviral therapy depending on the basis of medical record and filing system.
  4. Patients treated with interferon for any other cause.


Methods

Full ophthalmic examination was done for all patients including the following:
  1. Schirmer and tear film breakup time (TFBUT) tests to discover or exclude dryness.
  2. Coloured fundus photographs were achieved, and fluorescein angiography was fulfilled for cases with retinal abnormalities.


Tear film breakup time

A TFBUT value of more than 10 s is considered normal, a value of 8–10 s is believed to match with mild dryness, a value of 5–7 s is supposed to coincide with moderate dryness, and a value of less than 5 s is regarded as severe dryness.

Schirmer test

The Schirmer test has the following classifications:
  1. Normal, which is at least 15 mm wetting of the paper after 5 min.
  2. Mild dryness, which is 14–9 mm wetting of the paper after 5 min.
  3. Moderate dryness, which is 8–4 mm wetting of the paper after 5 min.
  4. Severe dryness, which is less than 4 mm wetting of the paper after 5 min.


Data management and analysis

The collected data were revised, coded, tabulated, and introduced to a PC using statistical package for the social sciences (SPSS 15.0.1 for Windows; SPSS Inc., Chicago, Illinois, USA). Data were presented, and suitable analysis was done according to the type of data obtained for each parameter.
  • P-value level of significance was as follows:
  • P value more than 0.05: nonsignificant.
  • P value less than 0.05: significant.
  • P value less than 0.01: highly significant.



  Results Top


There was no considerable variance between both study groups regarding age and sex ([Table 1]).
Table 1 Comparison between two groups regarding personal data

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There was no presumed variation between both study groups regarding baseline vision anterior and posterior segment condition ([Table 2]).
Table 2 Comparison between two groups regarding baseline clinical data

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There was no worthy contrast between both the study groups regarding baseline Schirmer, tear film breakup time (TFBUT) and intraocular pressure (IOP) results ([Table 3]).
Table 3 Comparison between two groups regarding baseline Schirmer, tear film breakup time and ocular tension

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There was no valuable dissimilarity between both the study groups regarding clinical data at 3 months ([Table 4]).
Table 4 Comparison between two groups regarding clinical data at 3 months

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There was no virtuous distinction between both the study groups regarding Schirmer test and ocular tension, with a significant decrease in TBUT in group 2 ([Table 5]).
Table 5 Comparison between the two groups regarding Schirmer, TBUT, and IOP at 3 months

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There was no important discrepancy between both the study groups regarding clinical data at 6 months ([Table 6]).
Table 6 Comparison between the two groups regarding clinical data at 6 months

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There was no significant incongruity between both the study groups ([Table 7],[Table 8],[Table 9]).
Table 7 Comparison between the two groups regarding Schirmer, TBUT and IOP at 6 months

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Table 8 Comparison between baseline, 3-month, and 6-month Schirmer test values among group 1 cases

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Table 9 Comparison between baseline, 3-month, and 6-month TBUT values among group 1 cases

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Retinopathy appeared 3 months after the treatment was started in 15% of group 2 cases and disappeared at 6 months, which dates 3 months after the treatment ends, which was statistically insignificant ([Table 10],[Table 11],[Table 12]).
Table 10 Comparison between baseline, 3-month, and 6-month posterior segment among group 2 cases

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Table 11 Comparison between baseline, 3-month, and 6-month Schirmer among group 2 cases

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Table 12 Comparison between baseline, 3-month, and 6-month BUT among group 2 cases

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  Discussion Top


Sofosbuvir was firstly created, produced and marketed in 2013. In the same year, the FDA approved sofosbuvir in conjunction with ribavirin for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injectable pegylated interferon and ribavirin for treatment of patients with HCV genotypes 1 and 4 [10].

This contemporary comparative study was implemented on 40 patients with chronic hepatitis C, 20 of them were registered for the oral dual-therapy strategy (study group 1: sofosbuvir and ribavirin) and the other 20 patients were enrolled for the oroparentral triple-therapy strategy (study group 2; IFN, ribavirin and sofosbuvir).

The mean age of study group 1 patients was 47±8.9 years with males representing 40% of cases whereas it was 45.45±8.85 years in study group 2 patients, with males representing 60% of cases, which is in agreement with Cuthbertson et al. [11], where mean age was 44±10.5 years, but slightly less than Salman [12] where mean age was 51±8.1 years.

In the study group 2, the incidence of retinopathy in the synoptic studied patients was assessed to be 15% (3/20). Studies by Jain et al. [13], Cuthbertson et al. [13], and Okuse et al. [14] have shown a slightly higher incidence of retinopathy ranging from 16 to 64% throughout the treatment with IFN; however Malik et al. [15], and Panetta et al. [16] showed relatively lower incidence of retinopathy (0 and 3.8%, respectively).

This study also demonstrated that retinopathy was in the form of cotton wool spots being bilaterally, peripapillary and midperipherally in the retina of the affected patients. These changes were in concordance with Schulman et al. [17] and Cuthbertson et al. [11].

The retinal lesions in our patients were insignificant as there was no deterioration in the best corrected visual acuity (BCVA) in all patients during the period of the study. These changes were in coincidence with Jain et al. [13], where none of their patients experienced any of the atypical ocular findings or compromised visual symptoms. Reversiblilty has been affirmed in our research as the cotton wool spots and dot haemorrhges receded when the affected patients followed up 3 months after the terminus of the regimen.

No previously reported associations with retinopathy exist in the literature regarding sofosbuvir. In the study group 1, the incidence of retinopathy was 0% compared with the 15% retinopathy incidence in the study group 2, which may be a sign toward IFN as the offending drug in retinopathy and decreases − even negates − the association between the drug sofosbuvir and retinopathy.

Regarding the best-corrected visual acuity and anterior segment in our treatise in both groups, no drastic changes have been discovered over the period of the study.

Concerning uveal tissue, neither anterior nor posterior uveitis has been declared in our project in both groups in accordance with that no previously reported associations between sofosbuvir and uveal tissue reaction in literature.

The ocular tension was within normal range in both study groups with no considerable difference between the two groups and also in each one at the interval of baseline and at 3 and 6 months later.

All in all and briefly, no abnormality has been accounted in the two study groups regarding anterior segment and posterior segment in lieu of cotton wool spots that developed among cases of study group 2.

In contrast, Tokai et al. [18] reported diverse other atypical interferon-associated ocular adverse effects such as neovascular glaucoma, periphlebitis, occulomotor nerve paralysis, optic disc oedema, cystoid macular oedema, subconjunctival, preretinal, and vitreous haemorrhage, retinal vein occlusion and panophthalmitis.

Our study shows no worthy contentions amongst both groups at the pretreatment baseline stage regarding ocular surface dryness tests, so there was no evidence of the enrolled patients to have dry eye before the start of antiviral drug therapy.

Schirmer test and TFBUT results changed significantly over the 6-month study period. In study group 1, it decreased at 3 month after the start of sofosbuvir antiviral drug therapy and continued to decrease throughout the period of follow-up.

On the contrary, in the study group 2, they decreased at 3 months after the treatment started but retrieved their common standard values 3 months after the treatment stopped.

Our study results concerning the dry ocular surface were in harmonization with Salman [12], who reported the recovery of Schirmer and TFBUT tests values after the antiviral treatment has been completed, pointing to the reversibility of dryness associated with IFN, ribavirin, and sofosbuvir.

In our research, both study groups show that the drug-induced dry eye effects were measly mild and had eternally little − even no − influences on one’s daily performance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Cuadros DF, Branscum AJ, Miller FD, Abu‐Raddad LJ. Spatial epidemiology of hepatitis C virus infection in Egypt: analyses and implications. Hepatology 2014; 60:1150–1159.  Back to cited text no. 1
    
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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.  Back to cited text no. 2
    
3.
American Association for the Study of Liver Diseases. Recommendations for testing, managing, and treating hepatitis C. Arlington: AASLD-IDSA; 2014.  Back to cited text no. 3
    
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.  Back to cited text no. 4
    
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Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, Jacobson IM. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878–1887.  Back to cited text no. 5
    
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De Clercq E. Dancing with chemical formulae of antivirals: a panoramic view (part 2). Biochem Pharmacol 2013; 86:1397–1410.  Back to cited text no. 6
    
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Moorjani H, Koenigsmann C, Kim MJ, Spaulding AC. Prisoners treated for hepatitis C with protease inhibitor, New York, USA. Emerg Infect Dis 2015; 21:186.  Back to cited text no. 7
    
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Nagaoka T, Yoshida A. Noninvasive evaluation of wall shear stress on retinal microcirculation in humans. Invest Ophthalmol Vis Sci 2006; 47:1113–1119.  Back to cited text no. 8
    
9.
Lim JW, Shin MC. Pegylated interferon‐associated retinopathy in chronic hepatitis patients. Ophthalmologica 2010; 224:224–229.  Back to cited text no. 9
    
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Orsi J, Einodshofer M, Kirkham H, Glover P, DuChane J. New all oral therapy for chronic hepatitis C virus (HCV): a cost-benefit analysis. Value Health 2014; 3:A37.  Back to cited text no. 10
    
11.
Cuthbertson FM, Davies M, McKibbin M. Is screening for interferon retinopathy in hepatitis C justified?. Br J Ophthalmol 2004; 88:1518–1520.  Back to cited text no. 11
    
12.
Salman AG. Ocular surface changes with sofosbuvir in Egyptian patients with hepatitis C virus infection. Cornea 2016; 35:323–328.  Back to cited text no. 12
    
13.
Jain K, Lam WC, Waheeb S, Thai Q, Heathcote J. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin. Br J Ophthalmol 2001; 85:1171–1173.  Back to cited text no. 13
    
14.
Okuse C, Yotsuyanagi H, Nagase Y, Kobayashi Y, Yasuda K, Koike K, Itoh F. 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.  Back to cited text no. 14
    
15.
Malik NN, Sheth HG, Ackerman N, Davies N, Mitchell SM. A prospective study of change in visual function in patients treated with pegylated interferon alpha for hepatitis C in the UK. Br J Ophthalmol 2008; 92:256–258.  Back to cited text no. 15
    
16.
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.  Back to cited text no. 16
    
17.
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.  Back to cited text no. 17
    
18.
Tokai R, Ikeda T, Miyaura T, Sato K. Interferon-associated retinopathy and cystoid macular edema. Arch Ophthalmol 2001; 119:1077–1079.  Back to cited text no. 18
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12]



 

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