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An eye on hepatitis C: a review

O olho na hepatite C: uma revisão

ABSTRACT

This review aims to caution ophthalmologists about the ocular consequences leading to the diagnosis of hepatitis C virus infection. In addition, in this context, the effects of old and new drugs are discussed in the ophthalmological setting. The importance of early diagnosis and the curative treatment of the disease has been reported in the national and international literature, demonstrating that its progression has important implications for daily clinical and surgical ophthalmological practice. Despite the scarcity of studies on new direct-acting antiviral drugs, fewer side effects of these drugs have been shown when compared with conventional interferon treatment with or without ribavirin. The ophthalmologist’s risk of becoming infected, as demonstrated by the presence of the virus in ocular structures, and the possibility of contamination, is also discussed.

Keywords:
Hepatitis C/ complications; Hepatitis C/drug therapy; Interferon/therapeutic use; Direct-acting antiviral drugs

RESUMO

Esta revisão objetiva alertar os oftalmologistas sobre as consequências oculares que levam ao diagnóstico da infecção pelo vírus da Hepatite C. Além disso, neste contexto, os efeitos de drogas antigas e novas são discutidos no cenário oftalmológico. A importância do diagnóstico precoce e do tratamento curativo da doença tem sido relatada na literatura nacional e internacional, demonstrando que sua progressão tem implicações importantes para a prática oftalmológica diária. Apesar da escassez de estudos sobre novos medicamentos antivirais de ação direta, foram demonstrados menos efeitos colaterais desses medicamentos quando comparados ao tratamento convencional com interferon, com ou sem ribavirina associado ou não à rivabirina. O risco do oftalmologista de se infectar, como demonstrado pela presença do vírus nas estruturas oculares, e a possibilidade de contaminação, também é discutido.

Descritores:
Hepatite C/complicações; Hepatite C/tratamento farmacológico; Interferon/uso terapêutico; Drogas antivirais de ação direta

INTRODUCTION

Hepatitis C virus (HCV) infection is a public health problem and one of the most common infections in humans. The HCV has a heterogeneous global prevalence, with areas of low, intermediate, and high predominance(11 World Health Organization. Guidelines for the screening, care, and treatment of persons with hepatitis C infection. Geneva: WHO; 2016.). Between 2% and 3% of the world’s population is estimated to be carriers of the virus, corresponding to 123-180 million infected people(22 Kretzer IF, do Livramento A, da Cunha J, Gonçalves S, Tosin I, Spada C, et al. Hepatitis C worldwide and in Brazil: silent epidemic- Data on disease including incidence, transmission, prevention, and treatment. ScientificWorldJournal 2014; 2014: 827849.).

A population-based study in Brazil involving only the state capitals demonstrated that the prevalence of infection varied between regions: North, 2.1%; Northeast, 0.7%; Central West, 1.3%; Southeast, 1.3%; South, 1.2%; and Federal District, 0.8%(33 Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde, Departamento de DST, Aids e Hepatites Virais. Hepatites virais no Brasil: situação, ações e agenda. Brasília (DF): Ministério da Saúde; 2010.).

HCV transmission is primarily parenteral. In the past, the primary sources of transmission were transfusions of blood and blood products before the virus was identified(44 Lavanchy D. The global burden of hepatitis C. Liver Int. 2009; 29(Suppl 1):74-81.). The incidence of the disease has declined steeply in recent years because transmission by blood and blood products is regulated in the vast majority of countries(55 Westbrook RH, Dusheiko G. Natural History of Hepatitis C. J Hepatol. 2014;61(1 Suppl):58-68.).

Despite the control of blood products, other mechanisms of transmission still remain(66 Lee MH, Yang HI, Yuan Y, L'Italien G, Chen CJ. Epidemiology and natural history of hepatitis C virus Infection. World J Gastroenterol. 2014;20(28):9270-80.). Geographical differences in risk factors exist for new notified cases. While unsafe practices among intravenous drug users constitute the primary mechanism of transmission in the U.S. and most industrialized countries(66 Lee MH, Yang HI, Yuan Y, L'Italien G, Chen CJ. Epidemiology and natural history of hepatitis C virus Infection. World J Gastroenterol. 2014;20(28):9270-80.), invasive procedures by health services have become the most important risk factors in other regions of the world(77 Martínez-Bauer E, Forns X, Armelles M, Planas R, Solà R, Vergara M, et al. Hospital admission is a relevant source of hepatitis C virus acquisition in Spain. J Hepatol. 2008;48(1):20-7.,88 Santantonio T, Wiegand J, Gerlach JT. Acute hepatitis C: Current status and remaining challenges. J Hepatol. 2008;49(4):625-33.).

Other less frequently reported mechanisms are occu­pational exposure, vertical transmission, and sexual contact with carriers of the virus(99 Chan J. Hepatitis C. Dis Mon. 2014;60(5):201-12.). A national survey coor­dinated by the Brazilian Society of Hepatology revea­led that hospital procedures are the primary risk factors for new HCV infections(1010 Ferreira AS, Perez RM, Ferraz ML, Lewis-Ximenez LL, Pereira JL, de Almeida PR, et al. Acute hepatitis C in Brazil: results of a national survey. J Med Virol. 2011;83(10):1738-43.).

Acute infection resolves spontaneously in 20-40% of cases, while the remaining infected individuals are chronic carriers of the HCV(1111 Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol. 2007;13(17):2436-41.). The risk of liver cirrhosis among chronic carriers is between 15% and 30% within 20-30 years. Cirrhosis and its complications, such as HCV-associated hepatocellular carcinoma (HCC), constitute approximately 700,000 deaths per year worldwide(1212 World Health Organization. Global Health Sector Strategy On Viral Hepatitis 2016-2021: Towards Ending Viral Hepatitis. Geneva: WHO; 2016.).

The current treatment for hepatitis C, which utilizes direct-acting antivirals (DAAs), cures the infection in >90% of patients, halting the progression of liver disease and significantly reducing the development of HCC(1313 Spengler U. Direct antiviral agents (DAAs): A new age in the treat­ment of hepatitis C virus infection. Pharmacol Ther. 2018;183:118-126.).

HCV infection is often asymptomatic until the onset of complications of liver cirrhosis(1414 Heller T, Rehermann B. Acute hepatitis C: a multifaceted disease. Seminars in liver disease. Semin Liver Dis. 2005;25(1):7-17.). Symptoms include extrahepatic manifestations associated with HCV, including cryoglobulinemia, salivary gland dysfunction, glomerulonephritis, thyroiditis, skin disorders, pulmonary fibrosis, Behçet disease, polyarthritis, fibromyalgia, Guillain-Barré syndrome, thrombocytopenic purpura, ocular disorders, and other less common conditions(1515 Nocente R, Ceccanti M, Bertazzoni G, Cammarota G, Silveri NG, Gasbarrini G. HCV infection and extrahepatic manifestations. Hepatogastroenterology. 2003;50(52):1149-54.

16 Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet. 2003;362(9401):2095-100.

17 Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryglobulinemia. N Engl J Med. 1992;327(21):1490-5.

18 Agnello V1, Elfahal M. Cryoglobulin types and rheumatoid factors associated with clinical manifestations in patients with hepatitis C virus infection. Dig Liver Dis. 2007;39(Suppl 1):25-31.
-1919 Ramos-Casals M, Loustaud-Ratti V, De Vita S, Zeher M, Bosch JA, Toussirot E, et al. Sjögren syndrome associated with hepatitis C virus a multicenter analysis of 137 cases. Medicine (Baltimore). 2005;84(2):81-89.). Such manifestations should prompt the physician to screen for the presence of the HCV because diagnosis of the infection and the currently available treatment may cure the infection, thereby preventing progression to cirrhosis and its associated complications.This review updates the reader about the magnitude of the problem and the implications for daily clinical and surgical ophthalmological practice.

Ophthalmologic changes associated with the HCV

Several disorders have been associated with chronic HCV infection. The primary site of ocular manifestation of the disease is the ocular surface, and the most common finding is keratoconjunctivitis sicca(2020 Jorgensen C, Legouffe MC, Perney P, Coste J, Tissot B, Segarra C, et al. Sicca syndrome associated with hepatitis C virus infection. Arthritis Rheum. 1996; 39:1166-71.

21 Zegans ME, Anninger W, Chapman C, Gordon SR. Ocular manifes­tations of hepatitis C virus infection. Curr Opin Ophthalmol. 2002; 13(6):423-7.

22 Mayo MJ. Extrahepatic manifestations of hepatitis C infection. Am J Med Sci. 2003; 325:135-48.
-2323 Cacoub P, Renou C, Rosenthal E, Cohen P, Loury I, Loustaud-Ratti V, et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. Medicine (Baltimore) 2000;79(1):47-56.). Several studies have reported a high frequency of dry eye syndrome(2424 Haddad J, Deny P, Munz-Gotheil C, Ambrosini JC, Trinchet JC, Pateron D, et al. Lymphocytic sialadenitis of Sjögren's syndrome associated with chronic hepatitis C virus liver disease. Lancet. 1992;339(8789):321-3.,2525 Pirisi M, Scott C, Fabris C, Ferraccioli G, Soardo G, Ricci R, et al. Mild sialoadenitis: a common finding in patients with hepatitis C virus infection. Scand J Gastroenterol. 1994;29(10):940-2.) associated or not with Sjögren syndrome (SS) when compared with the general population(2626 Verbaan H, Carlson J, Eriksson S, Larsson A, Liedholm R, Manthorpe R, et al. Extrahepatic manifestations of chronic hepatitis C infection and the interrelationship between primary Sjogren´s syndrome and hepatitis C in Swedish patients. J Intern Med. 1999; 245(2):127-32.

27 Siagris D, Pharmakakis N, Christofidou M, Petropoulos JK, Vantzou C, Lekkou A, et al. Keratoconjuntivitis sicca and chronic HCV in­fection. Infection. 2002;30(4):229-33.

28 Misiuk-Hojito M; Michalowska M; Banach I. Ocular manifestations during hepatitis C infection. Przegl Epidemiol. 2007;61(3):545-50.

29 Nawito Z, Amin A, El-Fadl SA, Abu El Einen K. Sicca complex among Egyptian patients with chronic hepatitis C virus infection. Clin Rheumatol. 2011;30(10):1299-304.
-3030 Tang L, Marcell L, Kottilil S. Systemic manifestations of hepatitis C infection. Infect Agent Cancer. 2016;11:29.). Other ocular manifestations have been documented, including keratitis, scleritis, and retinopathies(3131 Baratz KH, Fulcher SF, Bourne WM. Hepatitis C-associated keratitis. Arch Ophthalmol. 1998;116(4):529-30.,3232 Jacobi C, Wenkel H, Jacobi A, Korn K, Cursiefen C, Kruse FE. Hepatitis C and ocular surface disease. Am J Ophthalmol. 2007; 144(5):705-711.).

The pathogenesis of ocular changes is possibly due to the direct action of the virus and immunological reac­tions to certain viral antigens and even immune complexes(3333 Skopouli FN, Moutsopoulos HM. Autoimmune epitheliitis: Sjögren's syndrome. Clin Exp Rheumatol. 1994;12(Suppl 11):9-11.

34 Koike K, Moriya K, Ishibashi K, Yotsuyanagi H, Shintani Y, Fujie H et al. Sialadenitis histologically resembling Sjögren syndrome in mice transgenic for hepatitis C virus envelope genes. Proc Natl Acad Sci US A. 1997;94(1):233-6.
-3535 Conca P, Tarantino G. Hepatitis C virus lymphotropism and peculiar immunological phenotype: effects on natural history and antiviral therapy. World J Gastroenterol. 2009;15(19):2305-8.). The same explanation could apply to other HCV-associated extrahepatic manifestations, of which cryoglobulinemia is one of the more frequent manifestations, found in up to 50% of HCV carriers and most frequently presents as vasculitis in various organs(3333 Skopouli FN, Moutsopoulos HM. Autoimmune epitheliitis: Sjögren's syndrome. Clin Exp Rheumatol. 1994;12(Suppl 11):9-11.

34 Koike K, Moriya K, Ishibashi K, Yotsuyanagi H, Shintani Y, Fujie H et al. Sialadenitis histologically resembling Sjögren syndrome in mice transgenic for hepatitis C virus envelope genes. Proc Natl Acad Sci US A. 1997;94(1):233-6.

35 Conca P, Tarantino G. Hepatitis C virus lymphotropism and peculiar immunological phenotype: effects on natural history and antiviral therapy. World J Gastroenterol. 2009;15(19):2305-8.
-3636 Sherman AC, Sherman KE. Extrahepatic manifestations of hepatitis C infection: navigating CHASM. Curr HIV/AIDS Rep. 2015;12(3): 353-61.). The virus could also act as a trigger for autoimmune reac­tions, causing tissue damage and dysfunction(3737 Katsifis GE, Moutsopoulos NM, Wahl SM. T lymphocytes in Sjögren's syndrome: contributors to and regulators of pathophysiology. Clin Rev Allergy Immunol. 2007;32(3):252-64.). These alterations could also enable a pathologic manifestation in the posterior pole of the eye, such as retinopathy, papillitis, and neuritis(3838 Propst T, Propst A, Nachbauer K, Graziadei I, Willeit H, Margreiter R, et al. Paillitis and vasculitis of the arteria spinalis anterior as complications of hepatitis C reinfection after liver transplantation. Transpl Int. 1997;10(3):234-7.,3939 Anisia-Iuliana Al, Alina C, Elena CR, Dorin C. Ophthalmological implications of the chronic infections with the hepatitis C Virus. Rom J Ophthalmol. 2015;59(4):263-268.).

Ocular surface

Ocular surface alterations have been described in the literature for >20 years. Haddad et al. demonstrated alterations in 57% of patients with HCV (16 of 28 patients) versus 5% (1 of 20 patients) of controls(2424 Haddad J, Deny P, Munz-Gotheil C, Ambrosini JC, Trinchet JC, Pateron D, et al. Lymphocytic sialadenitis of Sjögren's syndrome associated with chronic hepatitis C virus liver disease. Lancet. 1992;339(8789):321-3.). Pawlotsky et al. also observed a higher frequency of such alterations in patients with HCV (14%) than in controls (0%)(4040 Pawlotsky JM, Ben Yahia M, Andre C, Voisin MC, Intrator L, Rou­dot-Thoraval F, et al. Immunological disorders in C virus chronic active hepatitis: a prospective case-control study. Hepatology. 1994;19(4):841-8.). Si­milarly, Jorgensen et al. reported dry eyes in 19% of pa­tients in a sample of HCV carriers(2020 Jorgensen C, Legouffe MC, Perney P, Coste J, Tissot B, Segarra C, et al. Sicca syndrome associated with hepatitis C virus infection. Arthritis Rheum. 1996; 39:1166-71.). In addition, Leyland et al. investigated whether chronic hepatitis C was associated with ocular disease in 25 patients with HCV, based on disease history assessment, the dry eye evaluation questionnaire, and the tear film break-up test (break-up time [BUT]). The results indicated changes in 44% of patients with a high incidence of altered BUT (≤10 seconds)(4141 Leyland M, Török ME, Acheson J, Foster GR. Hepatitis C virus infection is not associated with a marked increase in the prevalence of ophthalmic morbidity. Eye (Lond). 2000;14(Pt 6):889-91.). The associated salivary gland involvement with histological confirmation of SS has been linked to HCV(3434 Koike K, Moriya K, Ishibashi K, Yotsuyanagi H, Shintani Y, Fujie H et al. Sialadenitis histologically resembling Sjögren syndrome in mice transgenic for hepatitis C virus envelope genes. Proc Natl Acad Sci US A. 1997;94(1):233-6.). Verbaan et al. also evaluated salivary and ocular involvement among patients with HCV, observing that 67% of patients had at least 1 abnormal objective test indicative of keratoconjunctivitis or xerostomia, while 38% demonstrated lacrimal and salivary gland involvement(2626 Verbaan H, Carlson J, Eriksson S, Larsson A, Liedholm R, Manthorpe R, et al. Extrahepatic manifestations of chronic hepatitis C infection and the interrelationship between primary Sjogren´s syndrome and hepatitis C in Swedish patients. J Intern Med. 1999; 245(2):127-32.). Later, Cacoub et al. reported on 321 patients with HCV of whom 10% had dry mouth or dry eye(2323 Cacoub P, Renou C, Rosenthal E, Cohen P, Loury I, Loustaud-Ratti V, et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. Medicine (Baltimore) 2000;79(1):47-56.).

Recently, a more detailed study by Gumus et al. reported a higher frequency of changes in all Ocular Surface Disease Index (OSDI, Schirmer I, Schirmer II, and BUT) scores in patients with chronic hepatitis C than in noninfected individuals in an age- and sex-matched sample(4242 Gumus K, Yurci A, Mirza E, Arda H, Oner A, Topaktas D, et al. Evaluation of ocular surface damage and dry eye status in chronic hepatitis C at different stages of hepatic fibrosis. Cornea. 2009; 28(9):997-1002.).

Recently, 2 studies conducted in Brazil also emphasized the predominance of ocular surface alterations. Gomes et al. detected ocular surface disease in at least 1 eye in 88% of infected patients, exhibiting alterations in assessment parameters such as rose bengal staining (a vital dye that evaluates live epithelial cells without tear film protection) and the BUT test, in addition to observing altered stoichiometry (a test that evaluates corneal sensitivity) and less sensory perception in the eyes of infected patients(4343 Gomes RL, Marques JC, Albers MB, Endo RM, Dantas PE, Felberg S. Superfície ocular e hepatite C. Arq Bras Oftalmol. 2011;74(2):97-101.). In a study of 138 infected patients versus controls, Zeni et al. found altered BUT and Schirmer test results and observed higher mean tonometry values in the infected group(4444 Zeni LP, Viera PD, Michalczuk MT, Birkhan OA, Vilela MA, Álvares-da-Silva MR. Hepatitis C vírus induces abnormalities in surface and intraocular pressure: a comparative study. Eur J Gastroenterol Hepatol. 2013;25(4):411-5.).

The pathogenesis of dry eye in patients with HCV in­fection involves the destruction of glandular cells, possibly by antigenic reactions to immunocomplexes produced by viral antigens and specific antibodies or by the direct action of the virus(3232 Jacobi C, Wenkel H, Jacobi A, Korn K, Cursiefen C, Kruse FE. Hepatitis C and ocular surface disease. Am J Ophthalmol. 2007; 144(5):705-711.,4242 Gumus K, Yurci A, Mirza E, Arda H, Oner A, Topaktas D, et al. Evaluation of ocular surface damage and dry eye status in chronic hepatitis C at different stages of hepatic fibrosis. Cornea. 2009; 28(9):997-1002.). Other possibilities suggest that lymphocytic infiltration of the lacrimal gland(4545 Tsoumani A, Theopistos V, Katsanos K, Asproudis I, Tsianos EV. Treatment and non-treatment related ocular manifestations in patients with chronic hepatitis B or C. Eur Rev Med Pharmacol Sci. 2013;17(8):1123-31.,4646 Karaman Erdur S, Kulac Karadeniz D, Kocabora MS, Ozsutcu M, Gulkilik IG, Demirci G, et al. Ocular surface and tear parameters in patients with chronic hepatitis C at initial stages of hepatic fibrosis. Eye Contact Lens. 2015;41(2):117-20.) or modification of corneal sensitivity occurs due to sensory alterations in the trigeminal nerve, reducing tear production(4343 Gomes RL, Marques JC, Albers MB, Endo RM, Dantas PE, Felberg S. Superfície ocular e hepatite C. Arq Bras Oftalmol. 2011;74(2):97-101.).

Another ocular surface alteration associated with HCV infection is the presence of peripheral corneal ulce­ration, the so-called Mooren’s ulcer(4444 Zeni LP, Viera PD, Michalczuk MT, Birkhan OA, Vilela MA, Álvares-da-Silva MR. Hepatitis C vírus induces abnormalities in surface and intraocular pressure: a comparative study. Eur J Gastroenterol Hepatol. 2013;25(4):411-5.). Wenkel, Krist, and Korn identified the HCV in the tears of infected individuals. The proposed mechanism suggests that the peripheral cornea is affected by the presence of elevated immunoglobulin M, macrophage counts, Langerhans cell counts, and complement C1 fraction associated with high concentrations of HCV-RNA in tears and aqueous humor. Antigen-antibody complexes formed in the cornea near the limbal vessels or carried by tears trigger a chain of inflammatory reactions, especially in the peripheral cornea. In addition, immune complex deposition in the limbus causes immune vasculitis(4747 Wenkel H, Krist D, Korn K. Detection of hepatitis C virus RNA in tear film of patient with recurrent peripheral corneal ulcers. Klin Monbl Augenheilkd. 2001;218(6):459-62.).

The direct association of Mooren’s ulcer with HCV was challenged in studies by Wang et al. and Jain et al., who analyzed 50 patients positive for HCV for signs of keratitis, but found no such association(4848 Wang LJ, Zhou Y, Hu YQ, Chang ZR. [Epidemiological characteristics and prevention strategies of viral hepatitis in Chongwen District of Beijing during 1997-2006]. Zhonghua Yu Fang Yi Xue Za Zhi. 2008;42(8):592-5. Chinese.,4949 Jain AK, Sukhija J, Saini JS, Chawla Y, Dhiman RK. Hepatitis C virus- associated keratitis. Eye (Lond). 2004;18(2):131-4.); and Zegans et al. obtained the same result in 21 patients(1919 Ramos-Casals M, Loustaud-Ratti V, De Vita S, Zeher M, Bosch JA, Toussirot E, et al. Sjögren syndrome associated with hepatitis C virus a multicenter analysis of 137 cases. Medicine (Baltimore). 2005;84(2):81-89.). However, the clinical improvement of Mooren’s ulcer during treatment for hepatitis C, as observed by Erdem et al., suggests an association between the 2 conditions(5050 Erdem U, Kerimoglu H, Gundogan FC, Dagli S. Treatment of Mooren's ulcer with topical administration of interferon alfa 2a. Ophthalmology. 2007;114(3):446-9.).

The association between hepatitis C and keratitis is controversial; however, most researchers suggest that patients without rheumatologic disease, but with significant inflammatory reaction in the peripheral region of the cornea be screened for HCV infection(4444 Zeni LP, Viera PD, Michalczuk MT, Birkhan OA, Vilela MA, Álvares-da-Silva MR. Hepatitis C vírus induces abnormalities in surface and intraocular pressure: a comparative study. Eur J Gastroenterol Hepatol. 2013;25(4):411-5.,4949 Jain AK, Sukhija J, Saini JS, Chawla Y, Dhiman RK. Hepatitis C virus- associated keratitis. Eye (Lond). 2004;18(2):131-4.,5151 Wilson SE, Lee WM, Murakami C, Weng J, Moninger GA. Mooren´s corneal ulcers and hepatitis virus C infection (letter). N Engl J Med. 1993;329(1):62.).

HCV and the retina

Clinical studies have shown that retinopathies are associated with HCV(5252 Tu KL, Bowyer J, Scholfield K, Harding S. Severe interferon associated retinopathy. Br J Ophthalmol. 2003;87(2): 247-8.). In their study, Abe et al. reported retinopathy in 31.8% of 85 cases versus 6% of 100 controls. Alterations included retinal hemorrhage, both in the posterior pole and in the retinal periphery, in addition to cotton wool spots. Such alterations have been attributed to ischemia, which could be associated with infection-induced systemic vasculitis, phenomena similar to those occurring in diabetic retinopathy(4545 Tsoumani A, Theopistos V, Katsanos K, Asproudis I, Tsianos EV. Treatment and non-treatment related ocular manifestations in patients with chronic hepatitis B or C. Eur Rev Med Pharmacol Sci. 2013;17(8):1123-31.,5353 Guyer DR, Tiedeman J, Yannuzzi LA, Slakter JS, Parke D, Kelley J, et al. Interferon-associated retinopathy. Arch Ophthalmol. 1993; 111(3):350-6.,5454 Esmaeli B, Koller C, Papadopoulos N, Romaguera J. Interferon-induced retinopathy in asymptomatic cancer patients. Ophthalmology. 2001;108(5):858-60.), and intra-arterial obstruction due to embolization caused by leukoaggregates as a result of complement activation(5555 Sugano S, Suzuki T, Watanabe M, Ohe K, Ishii K, Okajima T. Retinal complications and plasma C5a levels during interferon alpha therapy for chronic hepatitis C. Am J Gastroenterol. 1998;93(12): 2441-4.), a mechanism also associated with the development of Purtscher-like retinopathy in patients with chronic HCV infection as demonstrated by peripapillary cotton wool spots and retinal pallor superficial to the macula(5656 Myers JP, Di Bisceglie AM, Mann ES. Cryoglobulinemia associated with Purtscher-like retinopathy. Am J Ophthalmol. 2001;131(6): 802-4.).

HCV and its associations with tumors of the eye and its adnexa

The association between hepatic cirrhosis as a result of the HCV and HCC is well established(5757 Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer. 1998;75(3):347-54.,5858 Kuper HE, Tzonou A, Kaklamani E, Hadziyannis S, Tasopoulos N, Lagiou P, et al. Hepatitis B and C viruses in the etiology of hepa­to­cellular carcinoma; a study in Greece using third-generation assays. Cancer Causes Control. 2000;11(2):171-5.) and attributed to both cirrhosis and the associated presence of the HCV as a carcinogen. The association between non-Hodgkin lymphoma and the HCV is described in previous studies(5959 Engels EA, Chatterjee N, Cerhan JR, Davis S, Cozen W, Severson RK, et al. Hepatitis C virus infection and non-Hodgkin lymphoma: results of the NCI-SEER multi-center case-control study. Int J Cancer. 2004;111(1):76-80.,6060 Marcucci F, Mele A. Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. Blood. 2011;117(6):1792-8.). Some ocular and orbital tumors, such as lacrimal gland lymphoma(6161 Coskun A, Yukselen O, Yukselen V, Karaoglu AO. Lacrimal gland marginal zone lymphoma: regression after treatment of chronic hepatitis C virus infection: case report and review of the literature. Intern Med. 2013;52(23):2615-8.) and rare tumors such as orbital plasmacytoma, are reported to be associated with the HCV(6262 Paul SB, Chalamalasetty SB, Vishnubhatla S, Madan K, Gamanagatti SR, Batra Y, et al. Clinical profile, etiology and therapeutic outcome in 324 hepatocellular carcinoma patients at a tertiary care center in India. Oncology. 2009;77(3-4):162-71.). Extranodal marginal zone lymphoma of MALT-type (MALT lymphoma), the subtype found most commonly in ocular adnexal lymphoma, is also associated with HCV infection(6363 Mitterlechner T1, Fiegl M, Mühlböck H, Oberaigner W, Dirnhofer S, Tzankov A. Epidemiology of non-Hodgkin lymphomas in Tyrol/Austria from 1991 to 2000. J Clin Pathol. 2006;59(1):48-55.).

Ocular changes related to HCV treatment

Hepatitis C treatment has utilized various strategies over the past 30 years. The primary strategies involved the use of interferon (IFN) combined with ribavirin, achieving cure rates of approximately 50%, but with many side effects(6464 Fried MW1, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975-82.). In 2011, the first generation of DAAs was in use, but still in combination with IFN, with cure rates of approximately 80%(6565 Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195-206.,6666 Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405-16.). However, despite the increased sustained virologic response, the severe side effects, especially with advanced disease, led to replacing this therapy with second-generation IFN-free DAAs in 2013, reaching virologic response rates of >90% without significant side effects(6767 Brandão-Mello CE. Tratamento da hepatite crônica pelo virus C: novas perspectivas. JBM. 2014;102(1):1-10.).

The drugs daclatasvir, sofosbuvir, simeprevir, dasabuvir, paritaprevir, ledipasvir, and ombitasvir, all DAAs, were included in the list of essential medicines of the World Health Organization (WHO) in 2015, and their use is regulated by the updated 2016 WHO Guidelines for the screening, care and treatment of persons with chronic hepatitis C infection(11 World Health Organization. Guidelines for the screening, care, and treatment of persons with hepatitis C infection. Geneva: WHO; 2016.).

Ocular changes associated with IFN and ribavirin treatment

Despite all the advances in the treatment of hepatitis C and the recommendation by the main WHO Guidelines for the preferential use of DAAs(6565 Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195-206.,6666 Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405-16.,6868 Wendt A, Adhoute X, Castellani P, Oules V, Ansaldi C, Benali S, Bourlière M. Chronic hepatitis C: future treatment. Clin Pharmacol. 2014;(6)1-17.), IFN is still part of the treatment regimens used in some regions of the world(6969 European Association for Study of Liver (EASL). Recommendations on Treatment of Hepatitis C 2016. J Hepatol. 2017;66(1):153-94.,7070 Brasil. Ministério da Saúde. Secretaria de Vigilancia em Saúde. Protocolo clínico e diretrizes terapêuticas para hepatite C e coinfecção. Brasília (DF); Ministério da Saúde; 2015.). IFN, an immunomodulatory cytokine, is pro­duced naturally by lymphocytes in response to viral infections(7171 Quesada Jr, Rios A, Swanson D, Trown P, Gutterman JU. Antitumor activity of recombinant-derived interferon alpha in metastatic renal cell carcinoma. J Clin Oncol. 1985;3(11):1522-8.), and when administered subcutaneously, it inhibits HCV replication and modulates the immune response against infected liver cells(7272 Parekh PJ, Shiffman ML. The role of interferon in the new era of hepatitis C treatments. Expert Rev Gastroenterol Hepatol. 2014; 8(6):649-56.).

The HCV treatment regimen recommended by Brazil’s Ministry of Health involves the use of DAAs. However, depending on the HCV genotype/subtype, some regimens still use IFN in its pegylated form (PEG-INF). In addition, recommendations by the European Association for the Study of the Liver justified the acceptance of PEG-INF by the heterogeneity of income per capita and health insurance systems throughout Europe and elsewhere. The high cost of new therapies is one of the primary barriers to their implementation(7373 Bidell MR, McLaughlin M, Faragon J, Morse C, Patel N. Desirable characteristics of hepatitis C treatment regimens: a review of what we have and what we need. Infect Dis Ther. 2016;5(3):299-312.).

Despite all the changes in hepatitis C treatment, ocular alterations triggered by using IFN with or without ribavirin are reported in many past and current studies(7474 Pazienza V. Ophthalmological complications in hepatitis C vírus infection: side effect of interferon therapy or a direct role of HCV. Biomed Pharmacother. 2011;65(4):317-8.,7575 Sharif W, Sheikh K, Silva I De, Elsherbiny S. Nonarteritic anterior ischemic optic neuropathy associated with interferon and ribavirin in a patient with hepatitis C Am J Ophthalmol Case Reports. 2017; 5:52-55.).

The incidence of IFN-associated retinopathy is variable, occurring in 18-86% of patients. For instance, Lima showed retinal changes in 35.7% (10 of 28) of patients receiving INF and in 33.3% (8 of 24) of those receiving PEG-INF(7676 Lima LC. Alterações oculares associadas ao tratamento sistêmico com interferon e PEG-interferon [dissertação]. Rio de Janeiro: Universidade Federal do Rio de Janeiro; 2005.). The deposition of immune complexes associated with lymphocyte infiltration in the retinal mi­crocirculation may be responsible for microvascular occlusion and focal ischemia(7777 Ávila MP, Freitas AM, Isaac DL, Bastos AL, Pena RV. Retinopatia em paciente portador de hepatite C tratado com interferon peguilado e ribavirina: relato de caso. Arq Bras Oftalmol. 2006;69(2):255-9.).

In addition to retinopathies, other alterations of the ocular posterior pole have been documented as related to HCV treatment, including macular edema, unilateral ischemic neuropathy, and bilateral anterior ischemic optic neuropathy, with blindness and choroidal and optic nerve infarction associated with polyarteritis nodosa(2828 Misiuk-Hojito M; Michalowska M; Banach I. Ocular manifestations during hepatitis C infection. Przegl Epidemiol. 2007;61(3):545-50.,7878 Kostina-O'Neil Y, Jirawuthiworavong GV, Podell DN, Lesser RL. Choroidal and optic nerve infarction in hepatitis C- associated polyarteritis nodosa. J Neuroophthalmol. 2007;27(3):184-8.). Vogt-Koyanagi-Harada (VKH) syndrome and panuveitis are also described in patients during IFN treatment(2121 Zegans ME, Anninger W, Chapman C, Gordon SR. Ocular manifes­tations of hepatitis C virus infection. Curr Opin Ophthalmol. 2002; 13(6):423-7.,7979 Soma M, Hirata A, Takahashi T, Okinami S. Relapse of Vogt-Ko­yanagi-Harada Disease during interferon-α and ribavirin therapy in a case of chronic viral hepatitis C. Case Rep Ophthalmol. 2011;2(1):5-9.). The diagnosis of VKH is confirmed by retinal fluorescein angiography, typically showing multiple dots in the retinal pigment epithelium, and bilateral serous retinopathy and serous retinal detachment in combination with papillitis and optic disc edema(8080 Al-Muammar AM, Al-Mudhaiyan TM, Al Otaibi M, Abdo A, Abu El-Asrar AM. Vogt-Koyanagi-Harada disease occurring during interferon-alpha and ribavirin therapy for chronic hepatitis C virus infection. Int Ophthalmol. 2010;30(5):611-3.).

Conjunctivitis is the primary ocular side effect of ri­bavirin. In addition, ribavirin increases the risk and severity of retinopathy when combined with IFN(8181 O'Day R, Gillies MC, Ahlenstiel G. Ophthalmologic complications of antiviral therapy in hepatitis C treatment. World J Gastroenterol. 2013;19(45):8227-37.). This potentiating effect of IFN can be ascribed to changes in the immune system in the balance between type 1 and 2 T-helper cells(8282 Martins T, Narciso-Schiavon JL, Schiavon Lde L. Epidemiology of hepatitis C virus infection. Rev Assoc Med Bras. 1992. 2011; 57(1):107-12.,8383 Hultgren C, Milich DR, Weiland O, Sällberg M. The antiviral compound ribavirin modulates the T helper (Th)1/Th2 subset balance in hepatitis B and C virus-specific immune response. J Gen Virol. 1998;79 (Pt 10):2381-91.).

It is well known that patients undergoing IFN treatment with or without ribavirin may develop ocular diseases, including asymptomatic ones. And as no epidemiolo­gical studies have described the incidence of these pathologies, such patients should be examined and monitored, particularly in the event of complaints or adver­se events(8484 Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis, natural history, treatment and prevention of hepatitis C. Ann Intern Med. 2000;132(4):296-305.). Tsolakos et al. suggest that patients with pre-existing retinopathy, especially patients with hypertension and diabetes, should be monitored monthly during the course of hepatitis C treatment(7474 Pazienza V. Ophthalmological complications in hepatitis C vírus infection: side effect of interferon therapy or a direct role of HCV. Biomed Pharmacother. 2011;65(4):317-8.,8585 Tsolakos A, Zalatimo N. Hepatitis C: review of diagnosis, management, and ocular complications from treatment. Optometry 2003; 74(8):517-23.,8686 Novelli FJ, Przysiezny A, Rosa EL, Garcia RF, Nóbrega MJ. Ophthalmologic findings in hepatitis C patients treated with pegylated interferon α-2b and ribavirin. Arq Bras Oftalmol. 2014;77(3):178-81.). Recommended eye examinations include visual acuity, slit-lamp biomicroscopy, and ophthalmoscopy(8787 Farel C, Suzman DL, McLaughlin M, Campbell C, Koratich C, Masur H, et al. Serious ophthalmic pathology compromising vision in HCV/HIV co-infected patients treated with peginterferon alpha-2a and ribavirin. AIDS. 2004;18(13):1805-9.).

Ocular changes associated with DAA treatment

There are few available studies on the side effects of new treatments for hepatitis C, especially in the ophthalmologic context.

A recent case report by Chin-Loy et al. provided the first description of retinopathy and uveitis associated with the use of ribavirin and sofosbuvir(8888 Chin-Loy K, Galaydh F, Shaikh S. Retinopathy and Uveitis Associated with Sofosbuvir Therapy for Chronic Hepatitis C Infection. Cureus. 2016;8(5):e597.). Physical examination findings included conjunctival injection, fine keratic precipitates, bilateral flare, and the presence of peripapillary cotton wool spots. The pathogenic mechanism has not been elucidated, but the authors believe that the ocular alterations are related more to the use of sofosbuvir as the decreased dose of ribavirin did not stop disease progression. Moreover, a synergistic action of sofosbuvir and ribavirin may be possible as demonstrated when the latter is combined with IFN(8888 Chin-Loy K, Galaydh F, Shaikh S. Retinopathy and Uveitis Associated with Sofosbuvir Therapy for Chronic Hepatitis C Infection. Cureus. 2016;8(5):e597.). Salman performed subjective (OSDI) and objective tests (Schirmer tests, BUT, and nucleus-to-cytoplasmic ratio analysis of conjunctival cells by cytology) in 150 patients treated with sofosbuvir + PEG-IFN/ribavirin (group 1) compared with 150 patients treated with PEG-IFN/ribavirin alone (group 2). The results demonstrated a significant difference in the tests performed before and during the treatment of patients in group 1 and between groups 1 and 2 during treatment, indicating greater ocular surface involvement and the development of dry eye in subjects treated with sofosbuvir(8989 Salman AG. Ocular Surface Changes With Sofosbuvir in Egyptian Patients With Hepatitis C Virus Infection. Cornea. 2016;35(3):323-8.).

Perello et al. published a case series comparing a group of 576 patients infected with HCV and treated with a combination of DAAs and a control group of 230 infected patients, of whom 23 were untreated and 213 were treated with an IFN-based regimen. The results found that 10 patients experienced reactivation of the herpes virus (HV), 2 of them with ocular presentation, and 1 of whom progressed to keratouveitis(9090 Perelló MC, Fernández-Carrillo C, Londoño MC, Arias-Loste T, Hernández-Conde M, Llerena S, et al. Reactivation of herpesvirus in patients with hepatitis c treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol. 2016;14(11):1662-1666.e1.). As no patient in the control group experienced HV reactivation, it appears that treatment with DAAs may lead to transient changes in immunity favoring viral reactivation in some patients, thus demonstrating the need for further studies to clarify the reactivation mechanisms and monitor the HV in these patients, particularly those who have undergone liver transplantation or are of advanced age. Vaccination against the varicella-zoster virus can be performed in non-transplanted patients after treatment(9191 Hales CM, Harpaz R, Ortega-Sanchez I, Bialek SR. Centers for Disease Control and Prevention (CDC). Update on recommendations for use of herpes zoster vaccine. MMWR Morb Mortal Wkly Rep. 2014;63(33):729-31.).

Although its mechanism remains unclear, the combi­nation of ledipasvir/sofosbuvir was related to the development of painless, unilateral, acute visual loss, with visual field deficits and optic disc edema, in a young patient without risk factors who was diagnosed with nonarteritic anterior ischemic optic neuropathy (NAION)(9292 Manoharan N, Subramanian PS. A case of non-arteritic anterior ischemic optic neuropathy after completion of Harvoni therapy. Am J Ophthalmol Case Rep. 2017;6:55-57.). Given the potential of DAAs to decrease the viral load, this treatment was able to reverse NAION induced by hepatitis C in the patient(9393 Prud'homme S, Nevens F, Casteels I. Bilateral simultaneous anterior ischemic optic neuropathy, an extrahepatic manifestation of hepatitis C cured with direct acting antivirals. GMS Ophthalmol Cases. 2016;6:Doc05.).

In the era of IFN-free regimens, the ocular consequences of DAA-based treatments are not clear. However, an increased use of this treatment regimen has generated further studies on the main risks to the visual and other systems. Therefore, medical ophthalmologists and other health professionals should be aware of the ocular effects of these new drugs.

HCV detection sites in the eye and risk of contamination

Kobayakawa detected the virus using polymerase chain reaction (PCR) in the aqueous humor during cataract surgery in some patients(9494 Kobayakawa S, Tochikubo T, Watanabe H, Nomura N. Hepatitis C vírus in the aqueous humor. Nippon Ganka Gakkai Zasshi. 1993; 97(9):1061-4.), and Shimazaki et al. detected the virus in tears and aqueous humor(9595 Shimazaki J, Tsubota K, Fukushima Y, Honda M. Detection of hepatitis C virus RNA in tears and aqueous humor. Am J Ophthalmol. 1994;118(4):524-5.). In a study examining corneoscleral discs from donors seropositive for hepatitis B and C viruses(9696 Sengler U, Reinhard T, Adams O, Gerlich W, Sundmacher R. Testing of corneoscleral discs and their culture media of seropositive donors for hepatitis B and C virus genomes. Graefes Arch Clin Exp Ophthalmol. 2001;239(10):783-7.), Sengler also detected viral particles in some tissues on PCR, but Laycock et al. did not detect anything in the samples(9797 Laycock KA, Wright TL, Pepose JS. Lack of evidence for hepatitis C virus in corneas of seropositive cadavers. Am J Ophthalmol. 1994;117(3):401-2.). However, Atas et al. recently identified the virus on PCR in both the aqueous humor and the tears of subjects with anti-HCV-positive antibodies(9898 Atas M, Karatepe Hashas AS, Demircan S, Sarıguzel FM, Baskan B1, Yuvacı I, et al. The investigation of HCV RNA in tear fluid and aqueous humor in patients with anti-HCV antibody positive who underwent cataract surgery. Ocul Immunol Inflamm. 2016; 24(3):297-301.).

Another study demonstrated a significant correlation between HCV carriers and the presence of the virus in the cornea, justifying the rejection of potential donors, although no studies have reported cases of HCV transmission via corneal transplantation(9999 Lee LM, Henderson DK. Emerging viral infections. Curr Opin Infect Dis. 2001;14(4):467-80.). Similar studies have emphasized the importance of performing molecular tests to detect HCV nucleic acids (HCV-RNA) in the donor cornea as the best method to detect the transmission potential(100100 Heck E, Dingrando A, Proctor C, Cavanagh HD. Viral HCV RNA reactivity of corneal cells in plasma HCV nucleic acid-positive eye donors. Cornea. 2013;32(4):506-7.).

The occupational risk of contracting HCV on contact with contaminated blood and fluids is well known. Studies have described cases of contamination through the face and eyes, reinforcing the need of preventive measures against HCV contamination(8282 Martins T, Narciso-Schiavon JL, Schiavon Lde L. Epidemiology of hepatitis C virus infection. Rev Assoc Med Bras. 1992. 2011; 57(1):107-12.).

The presence of the virus in ocular structures, together with the possibility of contamination through the ocular surface, makes HCV an agent of particular risk to the ophthalmologist.

CONCLUSION

Knowledge of the manifestations of the HCV in the eye may aid in the early detection of this serious infection. Many studies have confirmed the association of lacrimal gland dysfunction as a cause of dry eye, and, although less common, of pathological alterations of the posterior pole, especially of the retina, that can occur even during treatment.

Finally, this review reinforces the importance of early suspicion or detection of HCV infection during ophthalmologic examinations, in addition to alerting health professionals, including ophthalmologists, to the risk of contamination during procedures, examinations, and ocular surgeries.

  • Funding: No specific financial support was available for this study.

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Publication Dates

  • Publication in this collection
    24 Jan 2019
  • Date of issue
    Mar-Apr 2019

History

  • Received
    17 Apr 2018
  • Accepted
    15 Sept 2018
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