Can low-dose interferon prevent relapse of hepatitis C virus infection?

PUBLIC RELEASE DATE: 5-Mar-2014
Contact: Vicki Cohn
vcohn@liebertpub.com
914-740-2100
Mary Ann Liebert, Inc./Genetic Engineering News

New Rochelle, NY, March 5, 2014—Chronic hepatitis C virus (HCV) infection can lead to serious diseases such as cirrhosis and cancer of the liver, so viral clearance and prevention of relapse are important treatment goals. Low-dose oral interferon may reduce the risk of HCV relapse in patients with mild liver fibrosis according to a study published in Journal of Interferon & Cytokine Research, a peer-reviewed publication from Mary Ann Liebert, Inc., publishers. The article is available free on the Journal of Interferon & Cytokine Research website.

In "A Double-Blind Randomized Controlled Study to Evaluate the Efficacy of Low-Dose Oral Interferon-Alpha in Preventing Hepatitis C Relapse," Chuan-Mo Lee and coauthors from several universities and hospitals in Taiwan present the results of a clinical trial comparing the effects of 24 weeks of treatment with two doses of oral interferon-alpha or placebo in patients who achieved viral clearance after successful HCV therapy.

"This is a highly significant study relevant to the optimal use of IFN for HCV treatment," says Co-Editor-in-Chief Ganes C. Sen, PhD, Chairman, Department of Molecular Genetics, Cleveland Clinic Foundation, Ohio.

###

About the Journal

Journal of Interferon & Cytokine Research (JICR), led by Co-Editors-in-Chief Ganes C. Sen, PhD, and Thomas A. Hamilton, PhD, Chairman, Department of Immunology, Cleveland Clinic Foundation, is an authoritative peer-reviewed journal published monthly online with Open Access options and in print that covers all aspects of interferons and cytokines from basic science to clinical applications. JICR is an official journal of the International Cytokine and Interferon Society. Complete tables of content and a sample issue may be viewed online on the Journal of Interferon & Cytokine Research website.

About the Publisher

Mary Ann Liebert, Inc., publishers is a privately held, fully integrated media company known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research, including Viral Immunology, AIDS Research and Human Retroviruses, and DNA and Cell Biology. Its biotechnology trade magazine, Genetic Engineering & Biotechnology News (GEN), was the first in its field and is today the industry's most widely read publication worldwide. A complete list of the firm's 80 journals, books, and newsmagazines is available on the Mary Ann Liebert, Inc., publishers website.

Source

Impact of Combination Interferon Therapy on the Body Weight, Body Fat and Lean Body Mass of Chronic HCV Infected Patients

Journal of Antivirals & Antiretrovirals

Research Article
Open Access

Ibrar Alam1,2, Ijaz Ali1, Sajid Ali3, Iftikhar Alam4,5, Farzana1 and 1 Naseem1

Corresponding Author :
Sajid Ali
Assistant Professor, Centre of Biotechnology and Microbiology
University of Peshawar, Pakistan
Tel: 92-0346911693
E-mail: vet_sajid@yahoo.com

Received November 26, 2013; Accepted December 29, 2013; Published December 31, 2013

Citation: Alam I, Ali I, Ali S, Alam I, Farzana, et al. (2013) Impact of Combination Interferon Therapy on the Body Weight, Body Fat and Lean Body Mass of Chronic HCV Infected Patients. J Antivir Antiretrovir 6:001-005. doi: 10.4172/jaa.1000087

Copyright: © 2013 Alam I, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Keywords: Body composition; Body fat; Interferon therapy; Hepatitis C

Introduction

Hepatitis C is a contagious disease of liver caused by the hepatitis C virus (HCV) [1] which is an enveloped ribo-nucleic acid (RNA) virus with a diameter of 50 nm and is classified as a separate genus (Hepacivirus) within the Flaviviridae family. The prevalence of HCV infection is estimated to be 2.2-3.0% (130-170 million people) worldwide [2].

About 15 to 20% of HCV infections progress to potentially serious cirrhosis and end-stage liver disease [3]. Patients with cirrhosis often have an abnormal body composition with clinical signs of proteinenergy malnutrition and a relative increase in body weight due to ascites or edema [4-6]. Ascites is a condition that is becoming treatable with diuretics, albumin preparations, ascetic reperfusion, and transjugular intrahepatic portosystemic shunting, but the prognosis of patients with ascites remains poor [7,8]. According to all consensus guidelines (EASL 2011, NICE 2010, AASLD 2009), the current standard of care (SoC) for HCV is the combination of interferon (IFN) and/or ribavirin (RBV) for 24-48 weeks, depending primarily on the viral genotype, virological response (SVR) (defined as undetectable HCV RNA level at 6 months after treatment completion).

Interferon (IFN) has been extensively used for treatment of HCV. The current therapy for HCV infection in developing countries is combination of either Telaprevir or Boceprevir (Protease inhibitors) with Ribavirin (RBV) and Interferon (IFN) for genotype 1 patients. This therapy has shown improved cure rate (60-80 percent), a significant increase in compare to prior therapy with improved SVR and significant reduction in treatment time (12-36 weeks).

Approximately 10-15 % of patients are forced to discontinue IFN therapy due to side effects/adverse effects associated with the therapy/ The rate of treatment withdrawal has been reported to be substantially higher. In addition, dose reduction of IFN and/or RBV owing to side effects/adverse effects is in the range of 25-40 % of patients. Studies suggest that dose reduction should be implemented at the earliest possible stage, when slight signs of side effects/adverse effects are noted [9].

A large regional and global variability exists in the nature of side/ adverse effects associated with HCV. There is also difference hence in the strategies employed to mitigate the impact of side/adverse effects during the treatment. The most common side/adverse effects include influenza-like symptoms (such as fatigue, headache, fever, and rigors). These occur in virtually all patients after the first doses of IFN, but usually subside after the first month of treatment. Dermatologic effects (alopecia, dermatitis) and gastrointestinal symptoms (nausea, diarrhea) are also very frequent. The most prevailing severe side effects/adverse effects are hematologic, neuropsychiatric and autoimmune [10].

Fellay et al. [11] has reported that anemia as an adverse effect of IFN therapy, is common in as much as 30% of the treated patients. For evaluation of anemia, usually the lowest hemoglobin (Hb) values are recorded 6-8 weeks after treatment has been started and stay at the same level throughout the remaining therapy period. There are higher chances of severe anemia to occur, with hemoglobin levels as much below as<10 g/dL and approximately 10-15 % of patients suffer from severe anemia [11].

In most clinics and health care centers, patients are weighed almost at every visit. However measuring weight alone can be a misleading indicator of nutritional status, particularly in HCV patients, because lean body mass is lost in preference to fat and in addition to it, there is no way to distinguish between body fat (BF), and lean body mass (LBM) when weight measurements alone are used [12]. Serial weight measurements have been used by the Centers for Disease Control and Prevention (CDC) as a way to identify the wasting syndrome and predict the development of AIDS [13]. However, measurement of body weight alone failed to identify dramatic losses in body cell mass and other body composition parts [14]. Thus, further measures of body composition are also needed, to identify losses or gains of lean body mass, body fat or body cell mass associated with increased mortality [13]. The present study was aimed to prospectively evaluate effects of combination antiviral therapy on total body weight, body fat and lean body mass of HCV infected adult individuals.

To investigate the effect of antiviral therapy, we carried out a crosssectional prospective study, to evaluate changes in various parameters of body composition such as body weight, body fat (BF) and lean body mass (LBM).

Materials and Methods

The present study was conducted at the Institute of Biotechnology and Genetic Engineering (IBGE) KPK Agricultural University, Peshawar and Khyber Teaching Hospital (KTH), Peshawar, Khyber Pakhtunkhwa of Pakistan.

Inclusion criteria were: adult male, having HCV, non-diabetic with no other reported infectious and/or non-infectious diseases, non-smoker and non-drug-users. In addition only those patients were included who had no recent history of intentional or unintentional weight loss or changes in other body composition parameters. All those subjects were excluded who had a recent history of any metabolic complications and/or medical disorder. A total of 30 subjects of local Pashtun ethnicity participated willingly in the study. The subjects were divided into two groups. One group started with IFN-combination (On therapy group) while the other group did not take any therapy during the study period. IFN-α 2b dose was 3 mU thrice a week plus Ribavirin 1000 mg/day. All the patients of the study, who visited the OPD were assessed and interviewed thoroughly. The following procedures were adapted for data collection.

• Screening for diagnosis to make sure they are suffering from HCV

• 24-hours Dietary Recall (Performa)

• Biochemical Tests and differential blood counts.

• Body composition Assessment using Bio-electric Impedance (BIA)

Screening

Initially all the subjects were screened for anti-Hepatitis C virus antibodies by Immuno-Chromatographic Tests (ICT) (Abbot and Awrate). Samples diagnosed as positive by ICT technique were further evaluated using ELISA (BIOKIT, S.A, Barcelona-Spain) according to the manufacturer’s instructions. All the ELISA positive samples were processed for RNA extraction. According to manufactures’ instructions we extracted HCV RNA from 200 μl sample of serum by using Ana-gen RNA extraction Kit (Ana-gen, USA). Qualitative HCV RNA extraction and HCV genotyping was carried out according to our previous work [15]. All the products of PCR (1st and 2nd rounds) were analyzed on 1.8% agarose gel prepared in 0.5% TBE buffer, stained with Ethedium bromide. Using Alpha quant (Alpha Innotech) gels were photographed.

Assessment of body composition and determination of blood chemistry

BIA is recommended in measurement of body composition in healthy as well as individuals with chronic disease conditions [16]. Bioelectrical impedance analysis (BIA) was performed to measure body weight, body fat and lean body mass of the study subjects by using Bodystat® Quanscan 4000 Hydration/Body composition Monitoring Unit, Isle of man, UK [17].

Routine blood chemistry for albumin, ALT (Alanin Aminotransferase) and hemoglobin were determined.

The study was approved by the Board of Studies, IBGE, AUP. Written consents of willing to participate in the study were obtained from all patients.

Statistical analysis

The data were statistically analyzed using SAS (Version 7.0. SAS, USA). Data were expressed in mean (STD). Student’s t-test was performed to explore the difference between means of variables of interest. A p value of ≤ 0.05 was considered as significant.

Results

The current study was conducted to investigate the changes in body composition as a result of interferon (IFN) therapy in HCV positive patients. A total of 30 male patients participated in the study. These patients were divided into two distinct groups i.e. ‘on therapy’ group (N, 20) and ‘no therapy’ group (N, 10). HCV positive patients ‘on therapy’ used the IFN treatment and were followed for the 6 months of treatment. As a control, HCV positive patients on ‘no therapy’ were also followed for the 6 months after they were first diagnosed.

The age and other characteristics of the patients are presented in Table 1. The mean age (p=0.39), weight (p=0.64), and BMI (p=0.56) of the two groups of HCV positive patients at baseline did not differ significantly. Table 1 also shows the mean body fat, lean body mass, intracellular and extracellular body water and phase angle of HCV positive patients which shows a homogeneous population of the study with respect to age and body weight. As clear from Table 1, these values did not differ significantly for the two groups (p, for all trends>0.05).

Tables 2 and 3 show respectively, the mean values of nutrient intake (energy and protein), selected blood biochemistry (albumin, ALT, hemoglobin) and differential blood counts of the HCV positive patients at baseline. As can be seen, these figures did not differ significantly for the two groups of HCV positive patients (i.e. on therapy and no therapy) (p, for all trends>0.05).

The mean difference in body weight of HCV patients ‘on therapy’ and on ‘no therapy’ are shown in Figure 1. As shown, there was a significant (p ≤ 0.05) reduction in Body Weight (62.93 ± 8.27 Kg at baseline vs. 57.13 ± 7.54 Kg at month 6) in HCV patients ‘on therapy’ group, whereas, a non-significant decrease in body weight in HCV patients on ‘no therapy’ (61.31 ± 11.73 Kg at baseline vs.60.72 ± 13.81 Kg at month 6).

As evident from Figure 2 there was significant (p ≤ 0.05) reduction in body fat (11.4 ± 6.57 Kg at baseline vs. 9.1 ± 6.36 Kg at month 6) observed in HCV patients ‘on therapy’, whereas, a non-significant increase occurred in HCV patients on ‘no therapy’ (body fat 9.02 ± 2.8 Kg at baseline vs. 9.41 ± 2.55 Kg at month 6; p=0.213).

Figure 3 shows the changes in LBM in the HCV patients ‘on therapy’ (blue line) and HCV patients on ‘no therapy’ (red line). There was a significant (p ≤ 0.05) mean reduction in LBM in HCV patients on therapy (51.6 ± 8.93 Kg LBM at baseline vs. 48.0 ± 8.64 Kg LBM at month 6) (Figure 3). In HCV patients on ‘no therapy’, there was a nonsignificant difference between the LBM at baseline (51.86 ± 10.16 Kg) and at month 6 (51.87 ± 11.14 Kg) (Figure 3).

Discussion

Hepatitis C is highly prevalent in Pakistan [15]. Treatment options for Hepatitis C include conventional IFN alone or in combination with Ribavirin. However, IFN-based therapy has several diverse effects (manifested in the form of weight loss etc) due to which, most often the treatment is discontinued [9]. As has been considered previously, beside body weight body fat (BF), lean body mass (LBM), extracellular and intracellular water (ECW and ICW), phase angle, and body cell mass (BCM) are some important parameters for assessing the health and nutritional status of individuals [18-20].

Data on changes in body composition in patients with HCV infection before and during treatment are not reported extensively, particularly in developing countries, where the infection may have different dimensions of prevalence and therapeutic approaches. This study was conducted on HCV patients in order to investigate the immediate effects of interferon-α (IFN-α) therapy on some selected parameters of body composition. Data on body composition is an important factor for treatment decisions, especially if supplemental therapy is needed. IFN-α and/or ribavirin treatment in HCV has been reported to be very often associated with fatigue, cephalgia, weight loss, flu-like syndromes, and anorexia [21]. All these contraindication may have adverse implications for changes in nutritional status and body composition [22].

HCV infection may adversely affect energy balance of the body leading to a reduction of both somatic proteins of fat-free mass (FFM) and of visceral proteins in the elderly patients. In addition, body composition is altered in patients with HCV because of proteinenergy malnutrition, altered micronutrient status, and variable fluid homeostasis [22].

In our study the percentage of individuals that experienced a reduction in total body weight during interferon therapy are higher than the 11-29%, reported by other studies [21,23]. The original studies mainly relied on patients for reporting of weight reduction rather than on prospective measurement, this may result in the difference in the percentage of subjects that experienced weight loss. Alternatively, a loss more than a pre-specified mass or percentage of baseline in some analysis is defined as weight loss. The observations prepared by other studies are, however, reliable with our own. As an example, an experiment of eleven children that were on interferon therapy for HCV showed a weight reduction and nutritional status was impaired in all of the subjects [24]. Another study reported that a reduction of body weight was observed; at the end of 4 weeks 91.2% of the patients showed a reduction in weight, at 12 weeks 93.7%, at 24 weeks 94.7% and at the end of 48 weeks of treatment a reduction in weight was observed in 89.6% of the patients. At 4 weeks median weight losses were 2.3% of pretreatment weight, at 12 weeks 4.6%, at 24 weeks 6.3%, at 52 weeks 8.9% of the treatment. Median weight had increased to 96.4% of the pre-treatment 12 weeks after the completion of the treatment, and this had increased to 99% by 24 weeks [25].

As can be seen in our study (Figures 1-3), changes in body weight and other body compartments (i.e. body fat and lean body mass) occurred mostly in the first four months of the treatment. These results are consistent with those reported by Gottrand et al. [24] and Lebensztjen et al. [26]. The former reported weight loss in HCV patients during the first three months of IFN therapy, while the latter reported these changes mainly in the second month of therapy. The onset and timing of weight loss is important as decisions regarding continuation, cessation, or modification in the dose and treatment regimen depend on the time when and how changes in body weight start.

In our study, all patients ‘on therapy’ lost weight with the greatest effect being demonstrated early in treatment (months 2 - 4) (Figure 1). All patients ‘on therapy’ lost body fat and again the greatest effect being demonstrated early in treatment (months 2 - 4) (Figure 2). The loss in lean body mass (LBM) was also experienced by all patients ‘on therapy’; however, the loss in LBM was uniform throughout the study period (Figure 3). In the HCV positive subjects who were on ‘no therapy’, the mean body weight loss was 0.59 (± 0.018) Kg and the difference between mean body weight at month 6 (60.72 ± 12.80) and mean body weight at baseline (61.31 ± 12.86 SD) was not statistically significant (p=0.20). Similarly, no significant changes in body fat and lean body mass were recorded for patients with ‘no therapy’ (Figures 2 and 3, respectively).

Winding up, interferon therapy (IFN) results in weight loss as a side effect in hepatitis C infected individuals. Adding together, the therapy affects other compartments of body composition adversely. The study is limited in that it could recruit male patients only with relatively smaller sample size. Future studies based on the finding of the present study will include female subjects from possibly all segment of population to generalize the results.

References

1. Ray CG, Ryan KJ (2004) Sherris Medical Microbiology. McGraw Hill, New York, USA.

2. Lavanchy D (2009) The global burden of hepatitis C. Liver Int 29 Suppl 1: 74-81.

3. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH (2000) Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med 132: 296-305.

4. McCullough AJ, Mullen KD, Kalhan SC (1991) Measurements of total body and extracellular water in cirrhotic patients with and without ascites. Hepatology 14: 1102-1111.

5. Panella C, Guglielmi FW, Mastronuzzi T, Francavilla A (1995) Whole-body and segmental bioelectrical parameters in chronic liver disease: effect of gender and disease stages. Hepatology 21: 352-358.

6. Prijatmoko D, Strauss BJ, Lambert JR, Sievert W, Stroud DB, et al. (1993) Early detection of protein depletion in alcoholic cirrhosis: role of body composition analysis. Gastroenterology 105: 1839-1845.

7. Moore KP, Wong F, Gines P, Bernardi M, Ochs A, et al. (2003) The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology 38: 258-266.

8. Salerno F, Borroni G, Moser P, Badalamenti S, Cassarà L, et al. (1993) Survival and prognostic factors of cirrhotic patients with ascites: a study of 134 outpatients. Am J Gastroenterol 88: 514-519.

9. Dieterich DT, Rizzetto M, Manns MP (2009) Management of chronic hepatitis C patients who have relapsed or not responded to pegylated interferon alfa plus ribavirin. J Viral Hepat 16: 833-843.

10. Sulkowski M, Shiffman ML, Afdhal NH, Reddy KR, McCone J, et al. (2009) 10 Declines in Hemoglobin Is Associated with Sustained Virologic Response (SVR) Among HCV Genotype 1-Infected Persons Treated with Peginterferon (PEG)/Ribavirin (RBV): Analysis from the Ideal Study. Gastroenterology 136: A-790-A-791.

11. Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, et al. (2010) ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 464: 405-408.

12. Wanke C, Polsky B, Kotler D (2002) Guidelines for using body composition measurement in patients with human immunodeficiency virus infection. AIDS Patient Care STDS 16: 375-388.

13. Knox TA, Zafonte-Sanders M, Fields-Gardner C, Moen K, Johansen D, et al. (2003) Assessment of nutritional status, body composition, and human immunodeficiency virus associated morphologic changes. Clin Infect Dis 36: S63-S68.

14. Kotler DP, Tierney AR, Wang J, Pierson RN Jr (1989) Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 50: 444-447.

15. Khan NU, Ali I, Ahmad NU, Iqbal A, Rehman LU, et al. (2011) Prevalence of active HCV infection among the blood donors of Khyber Pakhtunkwa and FATA region of Pakistan and evaluation of the screening tests for anti-HCV. Virol J 8: 154.

16. Gordner RL, Selden C, Foster WR (1994) Bioelectric impedance analysis in body composition measurement: program and abstracts: December 12-14, National Institutes of Health.

17. Kahraman A, Hilsenbeck J, Nyga M, Ertle J, Wree A, et al. (2010) Bioelectrical impedance analysis in clinical practice: implications for hepatitis C therapy BIA and hepatitis C. Virol J 7: 191.

18. Chertow GM, Lazarus JM, Lew NL, Ma L, Lowrie EG (1997) Bioimpedance norms for the hemodialysis population. Kidney Int 52: 1617-1621.

19. Earthman C, Traughber D, Dobratz J, Howell W (2007) Bioimpedance spectroscopy for clinical assessment of fluid distribution and body cell mass. Nutr Clin Pract 22: 389-405.

20. Kaysen GA, Zhu F, Sarkar S, Heymsfield SB, Wong J, et al. (2005) Estimation of total-body and limb muscle mass in hemodialysis patients by using multifrequency bioimpedance spectroscopy. Am J Clin Nutr 82: 988-995.

21. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, et al. (2001) Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358: 958-965.

22. Antaki F, French MM, Moonka DK, Gordon SC (2008) Bioelectrical impedance analysis for the evaluation of hepatic fibrosis in patients with chronic hepatitis C infection. Dig Dis Sci 53: 1957-1960.

23. Fried MW (2002) Side effects of therapy of hepatitis C and their management. Hepatology 36: S237-244.

24. Gottrand F, Michaud L, Guimber D, Ategbo S, Dubar G, et al. (1996) Influence of recombinant interferon alpha on nutritional status and growth pattern in children with chronic viral hepatitis. Eur J Pediatr 155: 1031-1034.

24. Seyam MS, Freshwater DA, O'Donnell K, Mutimer DJ (2005) Weight loss during pegylated interferon and ribavirin treatment of chronic hepatitis C*. J Viral Hepat 12: 531-535.

26. Lebensztejn DM, Zagorecka E, Kaczmarski M, Piotrowska-Jastrzebska J (2001) [The assessment of nutritional status in children with chronic hepatitis B treated with interferon alpha]. Pol Merkur Lekarski 11: 29-31.

27. Fernandes SA, Gonzalez MC, Bassani L, Miranda D, Pivatto B, et al. (2013) Is the Phase Angle, a Prognostic Indicator for Nutritional Status in Cirrhotic Patients? J Antivir Antiretrovir S3:004.

Source

Hepatitis C virus infection in dialysis patients

REVIEW ARTICLE

Year : 2014  |  Volume : 25  |  Issue : 1  |  Page : 1-8

Hossein Khedmat¹, Mohsen Amini¹, Mohammad Ebrahim Ghamar-Chehreh¹, Shahram Agah^2
1 Baqiyatalah Research Center for Gastroenterology and Liver Disease, Baqiyatallah University of Medical Sciences, Tehran, Iran
² Colorectal Research Center, Tehran University of Medical Sciences, Tehran, Iran
Click here for correspondence address and email

Date of Web Publication 7-Jan-2014

Abstract

Despite the introduction of strict hygienic precautions preventing infection spread of hepatitis C virus (HCV) in dialysis settings, this infection is still prevalent among dialysis patients due to procedures making the patients vulnerable to infection through blood contamination. Treatment of HCV infection in dialysis patients is also less successful than that in the non-uremic population due to contraindication of using ribavirin, a main drug, in the infected patients. In this review article we aim to investigate the feasibility of the current antiviral therapies in dialysis patients infected with HCV infection.

How to cite this article:
Khedmat H, Amini M, Ghamar-Chehreh ME, Agah S. Hepatitis C virus infection in dialysis patients. Saudi J Kidney Dis Transpl 2014;25:1-8

How to cite this URL:
Khedmat H, Amini M, Ghamar-Chehreh ME, Agah S. Hepatitis C virus infection in dialysis patients. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2014 Jan 12];25:1-8. Available from: http://www.sjkdt.org/text.asp?2014/25/1/1/124455

Introduction

The World Health Organization estimates the global prevalence of chronic infection with hepatitis C virus (HCV) to be 3%, with wide epidemiological variation. ^[1] In patients under going maintenance hemodialysis (HD), the prevalence of HCV infection substantially increases to up to 90%, ^[1],[2] and this disease has been shown to be associated with severe complications from chronic hepatitis to fatal cirrhosis and hepatocellular carcinoma. ^[3] Furthermore, there are other malignancies associated with

HCV infection in some patient populations. ^[4] Moreover, data on the natural history of HCV infection in kidney disease patients demonstrate that these patients may have significant liver disease on liver biopsy, despite normal serum liver enzymes, ^[5] and it also reportedly impairs the quality of life of chronic HD patients. ^[6] Accordingly, eradication of HCV infection in this specific population is highly recommended. ^[7]

Interferon-based therapy, a standard treatment for HCV infection, has many drawbacks in HD patients, such as poor tolerance and marginal response. ^[8] Prescription of ribavirin in HD patients is generally contraindicated due to a risk of hemolytic anemia. ^[9] Pegylated interferon (PEG-IFN), which has a large polyethylene glycol moiety bound to IFN, has higher stability and prolonged systemic bio-availability ^[10] with more efficiency compared with regular IFN. ^[9] However, data on the efficiency and safety of PEG-IFN in end-stage renal disease (ESRD) patients are limited. There are also newly introduced agents, including telaprevir and boceprevir, which have been successfully employed to manage HCV infection in the non-dialysis context. ^[10],[11] However, there is an absolute scarcity of data on the efficacy and/or safety of these drugs in dialysis patients, although one study suggested that renal dysfunction does not affect the serum levels of boceprevir. ^[12]

We aim in this review article to discuss the course and management of HCV-positive patients on maintenance HD.

HCV Infection Course in HD Patients

Because of the chronic nature of HCV infection and the high rate of morbidities and mortalities in dialysis patients owing to their renal disease, the long-term evaluation of the natural history of HCV infection in this patient population has several limitations. However, evidence suggests that HCV infection increases all-cause mortality in dialysis patients, ^{[13],[14],[15],[16],[17]} and this risk of death exists irrespective of the type of dialysis. ^[18] In a meta-analysis, Fabrizi et al. ^[19] reported that the presence of anti-HCV antibody was an independent factor for death, with a relative risk of 1.57 in patients on maintenance dialysis. They also reported that dialysis patients with HCV infection are significantly more likely to develop hepatocellular carcinoma and liver cirrhosis. ^[19] On the other hand, renal transplantation has been recommended for HCV-positive dialysis patients because of its survival advantage over patients remaining in the waiting list, ^[20] although, not surprisingly, viral replication of HCV has been shown to adversely affect renal graft survival. ^[21] The proposed explanation for this observation is that HCV-induced hepatic necro-inflammation would be accelerated, especially after renal transplantation, due to immunosuppression therapy. ^[22]

 Diagnosis of HCV Infection in ESRD Patients

There are two types of assays that measure the anti-HCV antibodies: Enzyme immunoassay (EIA) and recombinant immunoblotting assay (RIBA). Although RIBA is a known confirmative test for the diagnosis of HCV infection in case of positive EIA samples, molecular assays detecting circulating HCV-RNA have thoroughly replaced it. It has been demonstrated that the false-negative rates of EIA-2 were too high, rendering the HCV-RNA polymerization as the gold standard test to confirm the HCV infection. ^[23],[24] However, the EIA-3, as a serological assay, has a high sensitivity in patients on maintenance dialysis and can be effectively used for HCV diagnosis in the HD population. ^[3]

Detection of serum aminotransferase levels in HCV-infected HD patients is of less value because it is suggested that ESRD itself lowers the aminotransferase levels; however, some authors suggested different cut-off levels for them in this patient population. , Although some authors suggested some clinical values for elevated aminotransferase levels in dialysis patients, multivariable analysis in one of them showed no independently significant relationship. ^[27]

The distribution of HCV genotypes widely varies in different geographical areas, although HCV genotype 1 predominates in dialysis patients with chronic HCV infection, regardless of geographic area. ^{[28],[29],[30]} Detection of HCV-RNA is the direct method of evaluating HCV infection. Moreover, this method enables us to estimate the viral replication rate in the liver; thus, it is a reliable test to assess the response to antiviral treatment and helps physicians determine the optimal duration and dosage of anti-viral agents. Most studies indicate that the HCV-RNA levels decrease transiently during HD sessions. ^[31] Several mechanisms have been suggested for this observation, including the adsorption of HCV onto the dialysis membrane, destruction of HCV particles, escape of HCV into the dialysate and an increase of plasma IFN-α levels during dialysis. ^[32],[33] However, recent studies have reported different observations such as a steady state or an increasing rate of HCV-RNA concentration during HD sessions. ^[34],[35] Interestingly, this observation was independent from HD procedures, dialysis membrane, heparin concentration and uremic toxins. ^[35]

Role of Histological Evaluation of the Liver

The histopathological evaluation of a liver biopsy specimen is of substantial value in determining the severity of liver fibrosis and necro-inflammation in chronic HCV infection. This also rules out other disorders, including the very prevalent non-alcoholic fatty liver disease, which may be able to induce similar damages to the liver. ^[36] However, liver biopsies are limited by complications including potentially mass bleeding events, patients' unwillingness and technical errors in obtaining the specimen or its evaluation. Compared with HCV patients with normal renal function, dialysis patients with HCV infection have milder hepatic necro-inflammation and fibrosis. The predictors of a hepatic damage in this patient population include a longer duration of infection, advanced age at infection, elevated serum aspartate aminotransferase (AST) and severe hepatic necro-inflammation on liver biopsy. ^[37] Clinical relevance of evaluating liver histopathology in dialysis patients includes the necessity for IFN-based therapy, the long-term prognosis and the eligibility for kidney transplantation. ^{[38],[39],[40]}

For dialysis patients on a transplantation waiting list, the Kidney Disease Improving Global Outcomes (KDIGO) recommends liver biopsies in the HCV-infected patients, while the American Association for the Study of Liver Diseases (AASLD) limits the biopsies to only the dialysis patients with genotypes 1 and 4 HCV infection. ^[42]

There is an increased risk of bleeding in patients with chronic kidney disease because of platelet dysfunction and anticoagulation therapies. Accordingly, the preferred method of a liver biopsy in HD patients is the trans-jugular or transfemoral routes. Moreover, through this method, one can also estimate the hepatic venous pressure gradient as well as the portal hypertension.

Treatment of Acute Infection with Hepatitis C Virus

Despite the introduction of a new generation of anti-HCV agents, IFN-α is still considered a very effective treatment in dialysis patients developing acute HCV infection according to recent publications. In a recent meta-analysis of eight clinical studies including 173 unique patients, Fabrizi et al ^[7] reported that IFN-based therapy of acute hepatitis C in dialysis populations results in a sustained virological response (SVR) in almost half of the patients. The patients who received higher doses of IFN developed higher rates of SVR. ^[44],[45]

In non-uremic patients, PEG-IFN-α-2b increases the SVR rate up to 94% in acute hepatitis C infection. ^[46] Nevertheless, data on the efficacy of PEG-IFN in dialysis patients are limited and suggestive of less-promising results than in non-uremic individuals. A recent study by Liu et al ^[47] on 35 HD patients who developed acute hepatitis C and did not have spontaneous HCV clearance by 16 weeks concluded that treatment with PEG-IFN-α-2a at a dosage of 135 μg weekly for 24 weeks was associated with almost 90% virological response, while this rate in 36 control patients who did not receive therapy was only 17%. In another study, 32 ESRD patients with acute HCV infection were followed and ten of them received PEG-IFN-α-2b, and only 40% developed SVR and one died. ^[48]

Treatment of Chronic Hepatitis C Virus Infection in Dialysis Patients

[Table 1] summarizes the data of previous metaanalyses on the treatment of chronic HCV infection in HD patients. Despite the introduction of more potent drugs and combination therapies of HCV infection in dialysis patients, IFN monotherapy is still considered a very effective therapeutic option in patients on maintenance dialysis. Conventional IFN monotherapy at a dose of 1-6 MU daily or three times per week for 12-48 weeks has been associated with SVR rates of 20-71% in dialysis patients. ^{[3],[49],[50],[51]} The predictive factors of SVR in these patients include a low baseline HCV-RNA level, mild liver histology and treating patients by IFN at a dose of 3 MU for at least six months.^[3],[52] Previous review articles have excellently included articles published earlier on the efficacy and safety of IFN monotherapy for chronic HCV infection in dialysis patients. ^[3] In our review, we only found one more article published recently to add. Fucuta Pereira Pda et al, ^[53] evaluating 40 HD patients, reported septal fibrosis or cirrhosis in 38% of patients. HCV-RNA was undetectable at Week 12 in 68% and SVR was observed in 30% of patients.

Table 1: Meta-analyses investigating efficacy of chronic HCV treatment in dialysis patients.

Peg-IFN has also been extensively used to treat chronic HCV infection in HD patients. Among recent studies, Kose et al. ^[5] investigated the largest patient population. PEG-IFN-α-2a 135 mcg/week was given for 48 weeks, which was administered in 41 patients, of whom 38 completed the study. Virological response rates for Weeks 12 and 72 were 60% and 50%, respectively. Furthermore, Alsaran et al. ^[2]treated 13 patients with PEG-IFN for 48 weeks, with no drop-out. After 24 weeks of therapy, 76% of patients responded to therapy and 24% of patients were resistant. Six months after termination of therapy, nine (69%) patients had SVR. ^[2] [Table 2] summarizes the recent studies investigating anti-HCV therapy in ESRD patients.

Table 2: Recent studies investigating treatment of HCV infection in dialysis patients.

Resistant Cases of Hepatitis C Virus-Infected Dialysis Patients to Interferon Therapy

Although treatment of HCV infection with IFN-based regimens in dialysis patients has been reportedly considered a safe and feasible method of therapy, many ESRD patients with HCV infection show resistance toward it. Intolerance to IFN due to its side-effects is the most significant cause of resistance to this therapy. There is a wide spectrum of side-effects associated with IFN therapy, which includes loss of appetite, fatigue, dry skin, influenzalike symptoms and gastrointestinal disturbances as well as neuropsychiatric symptoms and hematological abnormalities. ^[64] These side-effects often result in discontinuation or dose reduction of the drug, which can endanger viral response in HCV-infected dialysis patients. ^[55],[56] The incidence of these side-effects can be as high as 30% in patients using PEG-IFN, with lower rates in those using standard IFN. ^[64] Data on the efficacy and safety of PEG-IFN in ESRD patients are more limited and future studies are required to extend our knowledge on this issue.

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Source

Interferon-α/β for treatment of chronic hepatitis C infection in the era of direct-acting antiviral agents

Hepatology Research

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Review Article

Masaru Enomoto^*, Akihiro Tamori, Yoshiki Murakami, Norifumi Kawada

DOI: 10.1111/hepr.12289

This article is protected by copyright. All rights reserved.

Publication History
Accepted manuscript online: 11 DEC 2013 08:23PM EST
Manuscript Accepted: 6 DEC 2013

Keywords: DAA; direct-acting antiviral agents;  HCV;  hepatitis C;  IFN;  interferon

Abstract

Type I interferons (IFN-α/β), with or without ribavirin, have been the only agents that can eradicate the hepatitis C virus (HCV). An IFN-free regimen combining oral direct-acting antiviral agents (DAAs) will be approved soon for genotype 1 patients. Here we discuss the role of IFN-α/β in the forthcoming “era of DAAs” with consideration of limitations and concerns about IFN-free therapies. First, the therapeutic efficacy of first-generation DAAs varies among the different subtypes. While the rate of sustained virologic response (SVR) is 60–90% among patients with genotype 1b, the rate often falls short of 50% in patients with genotype 1a. IFN and ribavirin can still be indicated for patients with genotype 1a as a platform for combination with DAAs. Second, there is concern about the emergence of drug-resistance resulting from inappropriate use of DAAs. The clinical significance of preexisting resistant variants has not been elucidated. Drug resistance may affect the efficacy of next-generation treatments. An IFN and ribavirin backbone in combination with DAAs is an effective measure to prevent the emergence of drug resistance and/or to suppress preexisting resistant viruses. Third, it remains unknown whether the incidence of hepatocellular carcinoma (HCC) will be reduced in patients who achieve SVR with IFN-free regimens. In contrast, there are many reports in Japan demonstrating the preventive effects of IFN on the development of HCC. When patients do not achieve SVR with first-generation DAAs, low-dose IFN maintenance therapy is a treatment option until the next-generation therapy with pangenotypic potency and high genetic barrier becomes available.

Source

Ophthalmologic complications of antiviral therapy in hepatitis C treatment

World J Gastroenterol. 2013 December 7; 19(45): 8227-8237.

Published online 2013 December 7. doi: 10.3748/wjg.v19.i45.8227.

Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Roderick O’Day, Mark C Gillies and Golo Ahlenstiel.

Roderick O’Day, Golo Ahlenstiel, Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, NSW 2145, Australia

Roderick O’Day, Mark C Gillies, Clinical Ophthalmology and Eye Health, The University of Sydney, Sydney, NSW 2000, Australia

Golo Ahlenstiel, Storr Liver Unit, Westmead Millennium Institute, The University of Sydney, Sydney, NSW 2145, Australia

Author contributions: O’Day R and Ahlenstiel G designed the research; O’Day R, Gillies MC and Ahlenstiel G wrote and revised the article.

Correspondence to: Dr. Golo Ahlenstiel, Department of Gastroenterology and Hepatology, Westmead Hospital, Hawkesbury Road, Westmead, NSW 2145, Australia. golo.ahlenstiel@sydney.edu.au

Telephone: +61-2-98457705 Fax: +61-2-96357582

Received July 19, 2013; Revised October 13, 2013; Accepted October 19, 2013;

Abstract

Antiviral therapy consisting of interferon-alpha and ribavirin for chronic hepatitis C infection is associated with multi-system side-effects. Ophthalmologic complications are common and can be classified into two groups: interferon-associated retinopathy and atypical adverse events. Interferon-associated retinopathy has been investigated by multiple observational studies that have found widely divergent results. The clinical importance of this complication is, consequently, controversial. This review examines the literature with the specific goal of identifying the most important ophthalmologic issues facing the hepatologist prescribing antiviral therapy. Accordingly, it assesses the incidence of interferon-associated retinopathy, as well as its risk factors, pathogenesis, clinical manifestations and options for management using data from the observational studies. The likely benefit of a screening program, especially one targeting patients with the highest risk of developing interferon-associated retinopathy, is analysed. Atypical ophthalmologic adverse events occur less frequently than interferon-associated retinopathy during antiviral therapy for chronic hepatitis C infection. They often, however, lead to irreversible vision loss. We examine the reports of these adverse events - in individual case reports or case series and in the observational studies investigating interferon-associated retinopathy - to describe the spectrum of these adverse events, the likely outcome for patients and to highlight the most important areas of future clinical research.

Keywords: Interferon, Hepatitis C, Ocular complications, Retinopathy

Core tip: Interferon-associated retinopathy is usually a benign, transient phenomenon with no lasting impact on visual function. It occurs in approximately 30% of patients receiving antiviral therapy for chronic hepatitis C infection. The main risk factors for its development appear to be hypertension and diabetes. Unless a clear benefit to patients can be shown, a screening program for the development of interferon-associated retinopathy is not justified. No conclusive evidence exists for a causal link between it and the atypical adverse events of antiviral therapy, which tend to cause irreversible vision loss.

NTRODUCTION

With 160 to 170 million infected people worldwide, hepatitis C virus (HCV) presents a major health care problem[^1,2]. Current standard of care treatment consists of pegylated interferon alpha (PEG-IFNα) and ribavirin (RBV) for genotypes 2 to 6[^3,4]. Boceprevir or telaprevir may be added to these for gentopye 1 infections[⁵]. Standard of care therapy is associated with side effects in many organs, the majority of which are attributed to interferon. Ophthalmologic complications can be classified into two groups: interferon-associated retinopathy and atypical adverse events.

BACKGROUND

HCV, first identified in 1989, is a major cause of chronic liver disease[^6,7]. It is the most common indication for liver transplantation in the Western world[⁸]. The natural course of HCV infection results in chronic disease in approximately 70% of patients, with the remaining 30% clearing the infection spontaneously[⁹]. Patients with chronic hepatitis C (CHC) infection can transmit HCV and are at risk of progression to liver cirrhosis and/or hepatocellular carcinoma[¹⁰].

The treatment of chronic hepatitis C infection has evolved over the past 20 years. Interferon alpha (IFNα) monotherapy was the first drug regimen found to induce viral clearance[¹¹]. The combination of IFNα with oral RBV, a synthetic guanosine nucleoside, was subsequently found to increase the rate of viral clearance by 2-3 times[^12,13]. Pegylation, the process of attaching IFNα to a polyethylene glycol moiety, both increased viral clearance and decreased the frequency of dosing of interferon to once weekly injections[^14,15]. Most recently, treatment for HCV genotype 1 infection has been amended to include a third drug, either boceprevir or telaprevir, both of which are direct-acting antivirals[⁵].

INTERFERON-ASSOCIATED RETINOPATHY

Interferon-associated retinopathy was first described by Ikebe et al[¹⁶] in 1990. It has been widely investigated since then. Our literature review identified 22 English-language reports of observational studies assessing its incidence and clinical features[^17-38]. These studies all performed ophthalmological examinations during a course of antiviral therapy for chronic hepatitis C monitoring for interferon-associated retinopathy and atypical adverse events. They are summarised in Tables 1 and 2. Table 1 presents studies where more than half of the patients were treated with IFNα based regimens (n = 10), whereas Table 2 presents studies with majority PEG-IFNα treated patients (n = 12).

Table 1 Incidence of interferon-associated retinopathy in observational studies during which more than half of the patients are treated with interferon-α based regimens for chronic hepatitis C

Study	IAR incidence	Country	Timing of examinations	Comment
Nagaoka et al[17]	22 of 36 (61%)	Japan	Baseline, 2, 4, 8, 16 and 24 wk	IAR: no reduced VA in eyes that developed IAR. No dose reduction for management of IAR. Age was a risk factor for the development of IAR. HTN and DM were not. Atypical adverse events: nil reported.
d’Alteroche et al[18]	36 of 144 (25%)1	France	Baseline and then 3 monthly	IAR: No reduced VA in eyes that developed IAR. No dose reduction for management of IAR. HTN (9 of 11), receiving PEG-IFNα and older age were more likely to develop retinopathy. Insufficient numbers with DM (n = 1). Atypical adverse events: nil reported.
Okuse et al[19]	14 of 73 (19%)	Japan	Baseline, 2, 4, 12 and 24 wk	IAR: no reduced VA in eyes that developed IAR. No dose reduction for management of IAR. HTN significantly associated with development of IAR (5 of 15), T2DM not (1 of 2). Atypical adverse events: nil reported.
Schulman et al[20]	27 of 42 (64%)	United States	Baseline and then 2-3 monthly for 4-20 mo	IAR: therapy discontinued in two patients with multiple CWS, one with mild decrease in VA. All other patients with IAR continued with treatment. High doses of interferon used, up to 5MIU/d. HTN was not predictive of the development of IAR. Insufficient eyes for analysis of DM as risk factor (n = 2). Atypical adverse events: permanent peripheral monocular scotoma in 1 patient. Disc edema in 1 patient with a background of rheumatoid arthritis; no long term vision loss.
Jain et al[21]	8 of 19 (42%)	Canada	Baseline and then monthly	IAR: no change in VA in any patient with retinopathy. IAR resolved during study period in all but one patient. No dose reduction for management of IAR. Atypical adverse events: nil reported.
Saito et al[22]	28 of 81 (35%)	Japan	Baseline and then 2 weekly	IAR: no reduced VA in eyes that developed IAR. No dose reduction for management of IAR. IAR was more likely in older patients and those with DM and/or HTN. Atypical adverse events: nil reported.
Kadayifcilar et al[23]	7 of 20 (35%)2	Turkey	Baseline, monthly during treatment and 1 yr after completing treatment.	IAR: one of 7 with CWS at the macular had dose reduction by 1/2 for decreased VA. Full resolution in 4 wk. Otherwise no dose reduction for IAR. 16 of 20 patients had backgrounds of chronic renal failure. Atypical adverse events: unilateral BRVO in 1 patient with a background of CRF resulting in normal visual acuity at 12 mo but residual upper quadrantanopia.
Sugano et al[24]	6 of 25 (24%)	Japan	Baseline and then 4 weekly	IAR: not available. Atypical adverse events: not available.
Kawano et al[25]	36 of 63 (57%)	Japan	Baseline, 1, 2 and 4 wk and then 4 weekly until 6 mo after completing treatment	IAR: no dose reduction for 35 of 36 patients with IAR. Significantly higher incidence of retinopathy in patients with diabetes (11 of 12) and HTN (4 of 5). Atypical adverse events: severe RH in 1 patient with a background of DM; no long term vision loss.
Hayasaka et al[26]	14 of 40 (35%)3	Japan	1 mo prior to starting treatment and 2 weekly during treatment.	IAR: no reduced VA in eyes that developed IAR Not clear, but seems that interferon was ceased if developed IAR. Three patients with retinopathy at baseline all showed progression. Atypical adverse events: nil reported.

Twelve patients treated for chronic hepatitis B infection were excluded from the incidence data shown;

Sixteen patients treated for chronic hepatitis B infection were excluded from the incidence data shown;

Three patients that had baseline diabetic retinopathy were excluded from the incidence data shown. BRVO: Branch retinal vein occlusion; CRF: Chronic renal failure; CWS: Cotton wool spots; DM: Diabetes; HTN: Hypertension; IAR: Interferon-associated retinopathy; MIU: Million international units; PEG: Pegylated; IFN: Interferon; RBV: Ribavirin; RH: Retinal hemorrhage; VA: Visual acuity; VEGF: Vascular endothelial growth factor.

Table 2 Incidence of interferon-associated retinopathy in observational studies during which more than half of the patients were treated with pegylated interferon-α based regimens for chronic hepatitis C

Study	IAR incidence	Country	Timing of examinations	Comments
Mousa et al[27]	8 of 98 (8%)	Egypt	Baseline, 2, 4, 8, 12 and 24 wk then every 3 mo	IAR: seven of 8 patients with IAR had no reduction in VA. No dose reduction for management of IAR. Combined DM and HTN gave relative risk of 6.5 of developing IAR. Atypical adverse events: vitreous hemorrhage from retinal tears with retinal detachment requiring vitrectomy in 1 patient, final visual outcomes were not described.
Fouad et al[28]	22 of 84 (26%)	Egypt	Baseline, 12, 24 and 48 wk and 1 mo after completing treatment	IAR: no reduced VA in eyes that developed IAR. Three patients with IAR developed retinal hemorrhages and treatment was ceased. Logistic regression found HTN (9 of 12) and DM (13 of 16) to be predictors of developing IAR. Atypical adverse events: NAION in 2 patients and optic neuritis in 1 patient, final visual outcomes for these patients were not described.
Vujosevic et al[29]	21 of 97 (22%)1	Canada	Baseline, 3 and 6 mo and 3 mo after completing treatment	IAR: all patients with pre-existing retinopathy, 9 patients, had worsening of retinopathy during treatment. Factors associated with developing IAR were age, metabolic syndrome, HTN, cryoglobulinemia and pre-existing intraocular lesions. Using multivariate analysis only HTN was a significant predictor of developing IAR. Insufficient number of patients with DM (n = 5). Atypical adverse events: bilateral BRVO in one patient with a background of HTN resulting in irreversible vision loss in the left eye only.
Lim et al[30]	5 of 10 (50%)2	Korea	Baseline and then 3 weekly for 6 mo	IAR: no reduced VA in eyes that developed IAR. No dose reduction for management of IAR. Atypical adverse events: unilateral CRVO in 1 patient with a background of DM resulting in irreversible vision loss.
Mehta et al[31]	18 of 64 (28%)3	United States	Baseline, 3 and 6 mo	IAR: no reduced VA in eyes that developed IAR. 1 of 88 ceased treatment for asymptomatic IAR. Male only cohort. HTN and DM not significant predictor of developing IAR. Poor follow up rates - 69% had an eye exam within the first 12 weeks of starting treatment. Atypical adverse events: nil reported.
Kim et al[32]	11 of 32 (34%)	Korea	Baseline, 4, 8, 12, 16, 24, 36 wk	IAR: no reduced VA in eyes that developed IAR alone. No dose reduction for management of IAR. All retinal lesions spontaneously resolved. 91% of retinopathy developed within 2 mo, but 1 occurred at 4 mo. HTN significantly associated with development of IAR (6 of 10), T2DM not (1 of 2). Atypical adverse events: unilateral BRVO in 1 patient with background of HTN resulting in irreversible vision loss.
Panetta et al[33]	7 of 183 (4%)	United States	Baseline and repeat examination when visually symptomatic	IAR: three patients ceased treatment. Two with visual symptoms associated with IAR. 46% of patients had HTN and 16% had DM - neither predictive of developing IAR. Atypical adverse events: nil reported.
Malik et al[34]	3 or 38 (8%)	United Kingdom	Baseline, 3 and 6 mo. Low follow up rates	IAR: no reduced VA in eyes that developed IAR. No dose reduction for management of IAR. Atypical adverse events: nil reported.
Andrade et al[35]	5 of 34 (15%)	Spain	Baseline, at cessation of treatment and when visually symptomatic	IAR: no reduced VA in eyes that developed IAR. No dose reduction for management of IAR. Higher serum VEGF in patients with retinopathy and/or subconjunctival hemorrhage. Atypical adverse events: cystoid macular edema in 1 patient, final visual outcomes were not described.
Ogata et al[36]	25 of 69 (36%)	Japan	Baseline and then regularly for 6 months	IAR: no reduced VA in eyes that developed IAR. No dose reduction for management of IAR. 46% (13 of 28) treated with IFNα developed IAR compared to 29% (12 of 41) treated with PEG-IFNα. Atypical adverse events: no details.
Chisholm et al[37]	5 of 10 (50%)	United Kingdom	Baseline, 2, 4, 8, 12 and 24 wk and 12 wk after completing treatment	IAR: no dose reduction for management of IAR. Atypical adverse events: nil reported.
Cuthbertson et al[38]	4 of 25 (16%)	United Kingdom	3 mo after starting treatment or when visually symptomatic	IAR: no reduced VA in eyes that developed IAR. No dose reduction for management of IAR. Atypical adverse events: nil reported.

Nine patients that had baseline retinopathy were excluded from the incidence data shown. All 9 had progression of retinopathy;

Thirty-six of the 46 patients treated for chronic hepatitis B infection were excluded from the incidence data shown;

Ten patients that had baseline diabetic retinopathy were excluded from the incidence data shown. Five of these had resolution of retinopathy on subsequent eye exams. BRVO: Branch retinal vein occlusion; CRVO: Central retinal vein occlusion; DM: Diabetes; HTN: Hypertension; IAR: Interferon-associated retinopathy; NAION: Non-arteritic anterior ischemic optic neuropathy; PEG: Pegylated; IFN: Interferon; RBV: Ribavirin; VA: Visual acuity; VEGF: Vascular endothelial growth factor.

What are the clinical manifestations of interferon-associated retinopathy?

Interferon-associated retinopathy can be unilateral or bilateral and typical findings on slit lamp biomicroscopy or fundus photography are cotton wool spots and/or retinal hemorrhages (Figure 1). These lesions usually occur at the posterior pole within 2 disc diameters from the optic disc[^20,39]. Most commonly, it has a benign course with no impact on vision (Tables 1 and 2). It usually self-resolves during a course of antiviral therapy, or shortly thereafter, without requiring a reduction in dose (Tables 1 and 2).

Figure 1 Fundus photographs of a 60-year-old male treated with high dose interferon-α for renal cell carcinoma. These images show bilateral, typical interferon-associated retinopathy consisting of cotton wool spots and retinal hemorrhages surround the optic disc.

How common is interferon-associated retinopathy?

The observational studies have found a wide range of incidence of interferon-associated retinopathy during antiviral treatment for chronic hepatitis C infection, from under 4% to over 60% (Tables 1 and 2). Different protocols of ophthalmologic follow up and differences in patient populations are the most obvious causes of these divergent results. Other potential contributors to be considered are RBV combination therapy versus interferon monotherapy and whether different forms and doses of interferon-α are more likely to develop interferon-associated retinopathy.

Observational studies that had infrequent or symptom-initiated ophthalmologic examinations were more likely to find a lower incidence of interferon-associated retinopathy than those with more rigorous ophthalmologic follow up (Tables 1 and 2). Interferon-associated retinopathy most commonly develops between 2 and 12 wk after the initiation of antiviral therapy[^17,22,32,36]. It is a transient phenomenon lasting from a few weeks to years[^30,32,36]. Study protocols that did not examine patients multiple times within the first 6 mo of starting treatment were predisposed to underreport rates of interferon-associated retinopathy[^34,38]. Similarly, most patients who develop interferon-associated retinopathy have no visual symptoms (Tables 1 and 2). Thus, protocols that initiated ophthalmologic review only once a patient became symptomatic would, therefore, also result in underreporting[^33,35]. Four of the five studies reporting the lowest incidences of interferon-associated retinopathy displayed at least one of these two factors[^33-35,38].

Inclusion of patients with retinopathy at baseline skewed studies towards over-reporting of the incidence of interferon-associated retinopathy. No study has specifically assessed the clinical course of patients who have retinopathy from other causes prior to starting antiviral therapy, such as diabetes or hypertension. It is logical, however, that these patients would be at higher risk of having retinopathy during treatment than eyes without retinopathy at baseline. In the 22 observational studies considered in this review, 22 patients were identified as having retinopathy at baseline and 17 (77%) of these had progression of retinopathy[^26,29,31]. In one trial, half of the patients with retinopathy at baseline had resolution of retinopathy during treatment[³¹]. In the other trials that identified patients with retinopathy, all eyes with baseline retinopathy had progression during the course of treatment.

When patients with baseline retinopathy and studies with suboptimal ophthalmologic follow up are excluded, 313 of 1007 (31%) patients developed interferon-associated retinopathy with a range of 8%-64% (Tables1 and 2). The size of this corrected range implies that these factors do not fully explain the wide range of incidence of interferon-associated retinopathy.

Differences in the dose and type of interferon used in the observational studies have been proposed as key reasons for the wide range of incidence of interferon-associated retinopathy found. Early studies of IFNα for age-related macular degeneration found that the incidence of interferon-associated retinopathy was dose-dependent[⁴⁰]. Consistent with this, the study with the highest incidence analysed in this review used the highest dose of interferon: 3-10 million units IFNα subcutaneous injection daily[²⁰]. It has also been proposed that PEG-IFNα, which has a ten-fold longer serum-half life than conventional IFNα, may cause interferon-associated retinopathy more readily[³⁶]. This would contrast with the systemic side effect profile of PEG-IFNα, which appears to be similar to conventional IFNα[^14,15]. One large study found a significantly higher incidence of interferon-associated retinopathy in patients treated with PEG-IFNα than patients treated with IFNα of 45% vs 19%[¹⁸]. Two other smaller trials have found contradicting non-significant trends[^32,36]. Ultimately, the significance of this issue is questionable since it is unlikely that small differences in the incidence of interferon-associated retinopathy, which is largely benign, will alter these use of PEG-IFNα over IFNα or the dose used to treat chronic hepatitis C infection.

The effect of ribavirin on the incidence of interferon-associated retinopathy is unclear due to conflicting results found by the observational studies that addressed this issue. It is used for its synergistic effect with interferon therapy, but does not result in HCV eradication as a monotherapy[^12,13]. Conjunctivitis is the only ophthalmologic adverse event regularly associated with RBV[⁴¹]. It has, however, been suggested that combination therapy with RBV may increase the risk of interferon-associated retinopathy as compared to interferon monotherapy[^21,30]. Lim et al[³⁰] found a significantly higher rate of interferon-associated retinopathy in patients with chronic hepatitis C infection treated with PEG-IFNα and RBV combination therapy than patients with chronic hepatitis B infection treated with PEG-IFNα monotherapy, that is 50% vs14%. These results are difficult to interpret as chronic hepatitis C infection is associated with a hypercoagulable state, which itself may confer an increased risk of developing interferon-associated retinopathy[⁴²]. Further studies are required to determine the impact of RBV on the development of interferon-associated retinopathy.

Why does interferon-associated retinopathy occur?

The pathogenesis of interferon-associated retinopathy is yet to be fully elucidated. Its clinical manifestations, cotton wool spots and retinal hemorrhages suggest an ischemic mechanism. These changes are most commonly associated with diabetes or hypertension[^43,44]. It has been proposed that endothelial dysfunction, as evidenced by the failure of dilatation of retinal arterioles in response to wall shear stress in eyes that subsequently developed interferon-associated retinopathy, is the central process leading to retinal ischemia[¹⁷]. Endothelial dysfunction, it is proposed, causes platelet aggregation and leukocyte adherence to vascular endothelium[¹⁷]. These “immune complexes” act as microthrombi and cause focal retinal infarction[³⁹]. This hypothesis is supported by data suggesting IFNα may promote pro-thrombotic autoantibody production mediated by T cell activation[⁴⁵]. Further, IFNα may increase production of the highly potent intravascular aggregator of platelets, plasma-activated complement 5[²⁴]. Moreover, IFNα increases leukocyte adherence to the vascular endothelium resulting in leukocyte trapping in the retinal microcirculation[⁴⁶].

Does interferon-associated retinopathy causes vision loss?

Cotton wool spots and retinal hemorrhages are not usually associated with vision loss. They would if they occurred at the central macula, but the fovea centralis is avascular. Nevertheless, there are at least two reported cases of irreversible visual disturbance after interferon-associated retinopathy that consisted of cotton wool spots and/or retinal hemorrhages only, i.e. that were not associated with an atypical adverse event[^20,47]. One patient developed a permanent peripheral monocular scotoma in the same eye due to interferon-associated retinopathy consisting of cotton wool spots and retinal hemorrhages only[²⁰]. The other patient developed permanent bilateral reduced visual acuity and visual field defects after isolated interferon-associated retinopathy[⁴⁷]. Such cases, however, are rare; in most patients isolated interferon-associated retinopathy causes no impact on visual function (Tables 1 and 2). Indeed, in the 1289 patients, only 1 had interferon-associated retinopathy that caused vision impairment[²⁰] (Table 1). Importantly, vision loss that occurs whilst taking antiviral therapy is usually due to the development of an atypical adverse event.

Are there any groups that are at greater risk for developing interferon-associated retinopathy?

Hypertension and diabetes mellitus appear to be risk factors for the development of interferon-associated retinopathy; however, this has not been established unequivocally. Such a finding would be theoretically consistent with the proposed pathogenesis of interferon-associated retinopathy. The same methodological problems that resulted in the diversity in the incidence of interferon-associated retinopathy found by the observational studies described above also apply to this issue. Compounding this, the numbers of patients with diabetes or hypertension that developed interferon-associated retinopathy in most studies were too small to enable meaningful statistical analysis (Tables 1 and 2).

Observational studies of standard of care therapy for chronic hepatitis C infection during which at least 10 patients developed interferon-associated retinopathy identified diabetes and hypertension as its main risk factors[^28,29,31,32] (Table 2). Fouad et al[²⁸] performed a comprehensive study of 84 patients treated with standard of care therapy in Egypt with extensive ophthalmologic follow up. Their study, which included a number of patients with hypertension and diabetes, 12 and 16 respectively, found that both predicted the development of interferon-associated retinopathy using logistic regression analysis. By contrast, Mehta et al[³¹] found higher rates of interferon-associated retinopathy in patients with hypertension and diabetes, but the differences were not statistically significant. Their study had sufficient numbers of patients with these conditions - 13 patients with diabetes mellitus and 31 with hypertension - however, ophthalmological follow up was poor with less than 70% of patients receiving an eye exam within 12 weeks of starting standard of care therapy. Both Vujosevic et al[²⁹] and Kim et al[³²] performed observational studies with good numbers and adequate ophthalmologic follow up. They both found hypertension to be a significant predictor of the development of interferon-associated retinopathy using univariate and multivariate analysis. Diabetes mellitus was not found to be a significant predictor of the development of interferon-associated retinopathy using multivariate analyses in either, but the cohorts only had 5 and 2 patients with diabetes mellitus, respectively. In Vujosevic et al[²⁹], a higher percentage of patients with diabetes mellitus developed interferon-associated retinopathy on univariate analysis. There were insufficient numbers of patients with diabetes mellitus in earlier studies involving IFNα to assess its effect[^18-20]. Studies with adequate numbers of patients with diabetes mellitus tended to find it as a risk factor for the development of interferon-associated retinopathy.

No other patient characteristics that have been assessed have been found to predict the development of interferon-associated retinopathy (Tables 1 and 2). Older age has been suggested to represent a greater risk for its development, but this has not been a consistent finding[^17,19,22,29]. The larger studies that assessed risk factors identified above did not implicate age, with the exception of Fouad et al[²⁸], Vujosevic et al[²⁹], Mehta et al[³¹] and Kim et al[³²]. An association of age with the development of interferon-associated retinopathy may be because it is also associated with a higher risk of diabetes and hypertension.

If a patient develops interferon-associated retinopathy, what should be done?

There is a growing body of clinical experience that it is safe to continue standard of care therapy with no dose reduction in patients who develop interferon-associated retinopathy so long as they do not have reduced visual acuity or other visual symptoms which would suggest the development of an atypical adverse event (Tables 1 and 2). Various dose reduction and cessation regimens aiming to minimise the impact of interferon-associated retinopathy have been used. One study described the dose reduction regimens used by two clinicians in their management of 38 patients with interferon-associated retinopathy over 10 years[¹⁸]. This study did not compare outcomes between the groups. In fact, no formal comparator studies have assessed different strategies of managing standard of care dosing in patients who develop interferon-associated retinopathy. There is, therefore, no good evidence to guide whether interferon therapy should be modified or discontinued when interferon-associated retinopathy has been diagnosed. It is, however, well established that dose reduction of interferon increases the risk of treatment failure. Thus, dose reduction should be considered carefully.

Should we screen for interferon-associated retinopathy?

No consensus has been reached regarding the need to screen for interferon-associated retinopathy. Cuthbertson et al[³⁸] argue that due to the low incidence of interferon-associated retinopathy and its generally benign course there is no need for routine screening. By contrast, Vujosevic et al[²⁹] support a screening program targeting hypertensive patients, who they found to be at greater risk of developing interferon-associated retinopathy. Mousa et al[²⁷] propose that screening should only be for patients with both diabetes and hypertension, but not those with either in isolation. On the other end of the spectrum, Schulman et al[²⁰] considered close ophthalmological follow up for all patients as appropriate.

We propose that screening for interferon-associated retinopathy should only be performed if it meets the following criteria: (1) it can be used to predict the patients at risk for developing pathology that causes irreversible visual impairment; and (2) early treatment of these patients will reduce the chance of the development of that pathology. As discussed above, interferon-associated retinopathy, with a few exceptions, has a generally benign course. Screening for interferon-associated retinopathy may be justified if it can be proved that eyes that develop it are more likely to develop an atypical adverse event, which in turn causes poor visual outcomes. Evidence of such a relationship does not exist to date. In addition, it would need to be established that early detection would enable an intervention that reduces the severity of that atypical adverse event. For example, it would need to be shown that strict risk factor control after the diagnosis of interferon-associated retinopathy prevents the development of an atypical adverse event[⁴⁸]. With the current state of the evidence, a screening program for interferon-associated retinopathy, even one including only those patients at high risk of developing it, does not appear to be justified.

ATYPICAL ADVERSE EVENTS

Many atypical ophthalmologic adverse events have been encountered during antiviral therapy for chronic hepatitis C infection. The most common of these are retinal vein occlusion (RVO)[^{21,29,30,32,49-55}], and non-arteritic anterior ischemic optic neuropathy (NAION)[^28,49,56-59]. Other atypical adverse events that have been reported include ocular myasthenia[^60,61], optic neuritis[⁶²], Vogt-Koyanagi-Harada disease[^49,63-67], ocular sarcoidosis[^68,69], ocular toxocariasis[⁷⁰], neurovascular glaucoma[⁷¹], conjunctival hemorrhage[^20,26,35], macular edema[^72-74], oculomotor nerve palsy[⁷⁵], trichomegaly[²³] and retinal detachment[⁷⁶].

The mechanisms that cause an atypical adverse event may be distinct from the ischemic mechanism thought to be responsible for interferon-associated retinopathy. For example, there is growing evidence that interferon is directly toxic to the optic nerve[^62,77,78]. Chisholm et al[³⁷] found high levels of subclinical retinal toxicity, measured as aberration on multifocal electro-retinogram, in patients treated with IFNα and ribavirin. The electro-retinogram changes were not correlated with clinical signs of interferon-associated retinopathy, cotton wool spots an retinal hemorrhages[³⁷].

Atypical complications of antiviral therapy often result in dramatic, irreversible vision loss. In an exhaustive review of NAION that occurred during interferon therapy, half of the 36 documented cases of this complication suffered from permanent visual dysfunction[⁵⁶]. Similarly, in a recent review of RVO during interferon-α therapy, only 4 of 14 cases had full recovery of vision[⁵³]. Other atypical complications also lead to long-term visual impairment. In particular, inflammatory complications of antiviral therapy, such as Vogt-Koyanagi-Harada disease, also tend to have poor visual outcomes[^49,67]. In the 22 observational studies identified by our literature review involving 1287 patients treated with antiviral therapy for chronic hepatitis C infection, 12 (0.93%) patients developed an atypical adverse event. Five (0.39%) of these led to documented irreversible vision loss and 4 (0.31%) did not describe final visual outcomes (Tables 1 and 2).

The relationship between interferon-associated retinopathy and the atypical complications of antiviral therapy is unclear. Indeed, there is limited evidence that atypical adverse events are caused by interferon treatment and not merely due to chance[⁵⁶]. The most common complications, AION and RVO, are both vascular in nature. It has been suggested that there may be common elements between the pathogenesis of these complications and interferon-associated retinopathy[^49,56]. Certainly, there are many cases in the literature where AION and RVO are concomitant with interferon-associated retinopathy[^51,55,79]. As the atypical complications are the key causes of vision loss during antiviral therapy and interferon-associated retinopathy is common and well-described, any relationship between them should be explored in depth.

THE FUTURE

The standard of care regimen is in the process of a major re-evaluation after two major breakthroughs. Firstly, multiple HCV-specific direct-acting antivirals are at various stages of development and two of these have been approved for the treatment of genotype 1 HCV infection[^80-83]. Secondly, a host genetic polymorphism near the interleukin-28B (IL28B) gene on chromosome 19 that strongly predicts spontaneous and standard of care-induced recovery from infection was identified by four groups in 2009 and 2010[^84-87].

Despite the advent of direct-acting antivirals, it is likely that PEG-IFNα will remain an integral part to HCV treatment regimens for the foreseeable future[⁵]. When used as monotherapy, rapid virological resistance develops in vivo to the first generation direct-acting antivirals - telaprevir and boceprevir - inhibiting antiviral response[⁸⁸]. Moreover, the antiviral activity of these first generation direct-acting antivirals, the only approved by the FDA, appears genotype specific[⁸⁹]. Accordingly, they are presently recommended for use in genotype 1 chronic HCV only[⁵]. Investigations of second generation direct-acting antivirals are currently under way, so eventually we very likely will have interferon free-regimens[^90,91]. RBV, however, remains a core component of most of these regimens.

A controversial issue at present is whether patients, particularly those with IL-28B non-responder genotypes, should defer treatment for chronic hepatitis C infection until new, more effective regimens become available[⁹²]. Considering that the most common interferon-associated retinopathy seems to be largely benign in most patients, we do not feel that there is enough evidence for the potential risk for ophthalmologic complications to significantly impact this discussion as the most common is largely benign and there is no obvious, established link between interferon and the rarer, more severe adverse events.

CONCLUSION

In summary, the most common complication of antiviral therapy for chronic hepatitis C infection is interferon-associated retinopathy. This is usually a benign, self-limiting phenomenon with no lasting impact on visual function. It occurs in approximately 30% of patients undergoing standard of care therapy, however, there is significant variability in its incidence in observational studies. Hypertension and diabetes mellitus appear to be the most important risk factors for its development. The rarer, atypical adverse events of antiviral therapy often cause irreversible vision loss. The most common of these are RVO and NAION. To date, no definitive pathogenic link has been proven between antiviral therapy or interferon-associated retinopathy and any of the various atypical adverse events. If such a relationship can be found, screening for interferon-associated retinopathy may be justified as a means to prevent the development of an atypical adverse event. Newer direct-acting antivirals are likely to outpace further study into this area, making interferon-free antiviral therapy likely in the next 5 years.

ACKNOWLEDGMENTS

Associate Professor Justin O’Day for providing the illustrations in Figure 1.

Footnotes

Supported by National Health and Medical Research Council Project Grant, No. APP1006759 and the Robert W. Storr Bequest to the Sydney Medical Foundation of the University of Sydney to Ahlenstiel G

P- Reviewers: Dai CY, Fadda V S- Editor: Wen LL L- Editor: A E- Editor: Ma S

References

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