Ijaz S Jamall, Risk-Based Decisions, Inc., 2033 Howe Avenue, Suite 240, Sacramento, California 95825, United States
Shafaq Yusuf, Maimoona Azhar, Dow Medical College and Civil Hospital, Karachi, 74000, Pakistan
Selene Jamall, University of California-San Diego, La Jolla, CA 92092, United States
Author contributions: Jamall IS developed the approach and hypothesis and wrote much of the initial draft; Yusuf S and Azhar M provided clinical experience and relevance; Jamall S was a student intern with RBDI who conducted the literature search, data evaluation and helped in the writing of the final manuscript.
Supported by Risk-Based Decisions, Inc
Correspondence to: Ijaz S Jamall, Risk-Based Decisions, Inc., 2033 Howe Avenue, Suite 240, Sacramento, California 95825, United States. firstname.lastname@example.org
Telephone: 001-916-923-0570 Fax: 001-916-923-0611
Received: August 5, 2008 Revised: November 12, 2008
Accepted: November 19, 2008
Published online: November 21, 2008
Over the past decade, significant improvements have been made in the treatment of chronic hepatitis C (CHC), especially with the introduction of combined therapy using both interferon and ribavarin. The optimal dose and duration of treatment is still a matter of debate and, importantly, the efficacy of this combined treatment varies with the viral genotype responsible for infection. In general, patients infected with viral genotypes 2 or 3 more readily achieve a sustained viral response than those infected with viral genotype 1. The introduction of a pegylated version of interferon in the past decade has produced better clinical outcomes in patients infected with viral genotype 1. However, the published literature shows no improvement in clinical outcomes in patients infected with viral genotypes 2 or 3 when they are treated with pegylated interferon as opposed to non-pegylated interferon, both given in combination with ribavarin. This is significant because the cost of a 24-wk treatment with pegylated interferon in less-developed countries is between six and 30 times greater than that of treatment with interferon. Thus, clinicians need to carefully consider the cost-versus-benefit of using pegylated interferon to treat CHC, particularly when there is no evidence for clinically measurable benefits in patients with genotypes 2 and 3 infections.
© 2008 The WJG Press. All rights reserved.
Key words: Hepatitis C; Genotypes; Interferon
Peer reviewer: Anna Linda Zignego, Professor of Medicine, MASVE Center, Department of Internal Medicine, University of Florence, School of Medicine, Viale Morgagni 85, 50134, Florence, Italy
Jamall IS, Yusuf S, Azhar M, Jamall S. Is pegylated interferon superior to interferon, with ribavarin, in chronic hepatitis C genotypes 2/3? World J Gastroenterol 2008; 14(43): 6627-6631 Available from: URL: http://www.wjgnet.com/1007-9327/14/6627.asp DOI: http://dx.doi.org/10.3748/wjg.14.6627
The hepatitis C virus (HCV) is a non-cytopathic member of the Flaviviridae family that causes acute and chronic hepatitis and can lead to the development of hepatocellular carcinoma (HCC). An estimated 3% of the world’s population is infected with HCV. Acute infection is usually asymptomatic, which makes early diagnosis difficult. A distinct feature of HCV infection is its proclivity towards becoming chronic in as many as 70% of acute infections. Importantly, chronic hepatitis C (CHC) is associated with the progressive development of fibrosis and cirrhosis that, if left untreated, can lead to end-stage liver disease with an estimated 5%-20% mortality rate.
PREVALENCE AND VIRAL GENOTYPE
Preliminary surveys from Pakistan suggest that the seroprevalence of HCV is > 5%, while other surveys suggest rates as high as 10%[2-6]. In one study of prospective blood donors in Faisalabad, Pakistan, 78/294 individuals or 26.5% were found to be seropositive for HCV. If representative, this would be appreciably greater by far than the prevalence rate of 2.9% estimated for Egypt, a country with one of the highest HCV infection rates.
The predominant form of HCV infections in Pakistan is of the genotype 3 variety, and this genotype is also predominant in northern, northeastern, and central India, with infection rates as high as 71% in acute hepatitis patients, and as high as 82% in chronic hepatitis patients[9,10]. From a global public health perspective, sizeable fractions of CHC populations outside southern Asia are also infected with viral genotypes 2 and 3. For example, 26.9% of CHC patients in Serbia and Montenegro have been reported to be infected with genotypes 2 or 3. An estimated 37% of 90 consecutive liver patients from Novara, Italy, had genotype 2. In Cordoba, Argentina, 55% of 96 consecutive liver patients had genotype 2 and 5% had genotype 3. An estimated HCV prevalence of 31% for genotype 3 and 4.3% for genotype 2 has been reported in Brazil. These data from the more densely populated areas of the world suggest that the actual number of people infected with either genotype 2 or 3 is quite substantial compared to those with genotype 1, the predominant form in North America and northern Europe, although an estimated 16% of CHC patients in the United States are also infected with genotypes 2 or 3, as compared to 72% with genotype 1 (http://www.hepatitis.va.gov/vahep?page=diag-tests-03-05).
TREATMENT OPTIONS AND CLINICAL OUTCOMES
In the past two decades,
considerable progress has been made in the treatment of this disease
with the introduction of interferon (IFN), and, subsequently, with the
addition of the guanosine analogue, ribavarin (RBV), in 1998. Typically,
patients are treated with IFN by subcutaneous injection three times per
week in conjunction with a daily oral dose of RBV (800-
Correlations between serum virus levels, serum ALT levels, and liver pathology, while generally acceptable[15,16], have not been definitively established. The primary measure of current therapy is the achievement of virtually no detectable levels of HCV in serum at least 24 wk following the end of therapy, defined as the SVR. The SVR correlates well in clinical practice with patient recovery and wellbeing.
In the past decade, it has been reported that the addition of a polyethylene glycol (Peg) moiety to IFN (termed, Peg-IFN) significantly enhances its half-life in the blood, such that patients can be dosed with the Peg-IFN once weekly as compared to three times a week for the non-pegylated IFN.
In a study of 531 CHC patients (190 of whom were HCV genotype 2 or 3, and 329 were genotype 1), treated with Peg-IFN or IFN, without RBV, for 48 wk and followed up for an additional 24 wk, the overall SVR at 72 wk was 39% (95% CI, 33%-45%) for Peg-IFN and 19% (95% CI, 14%-24%) for IFN. The data were not separated by genotype. The authors noted that the rate of relapse between weeks 48 and 72 was higher among patients who had a response to Peg-IFN compared to those treated with IFN. In a randomized double-blind study of 1219 patients treated with Peg-IFN alone compared to IFN, both administered without RBV, significant improvements, including SVR, were noted in patients with genotype 1 virus, with a trend towards an improved, although not significant, response in patients with genotypes 2 and 3.
Treatment of CHC patients with Peg-IFN + RBV (the RBV dose typically weight-based but sometimes flat-dosed between 800 and 1200 mg/day, per os) has been shown to result in appreciably better clinical outcomes and has been touted as the so-called gold standard in the treatment of CHC. This conclusion stems almost exclusively from two studies[19,20] in which CHC patients were treated with Peg-IFN + RBV or with IFN + RBV. The data from these two studies have shown that the single greatest advantage of the Peg-IFN over IFN, both given in combination with RBV, has been the achievement of a statistically significant SVR in CHC patients with genotype 1, the recalcitrant form of this viral disease. The studies showed no consistent advantage of Peg-IFN over IFN (either one given in combination with RBV) in patients with viral genotypes 2 or 3. In the Manns et al study, the SVR was 76% for genotypes 2 or 3 and ranged from 36 to 56% in genotype 1 patients treated with IFN + RBV or Peg-IFN + RBV. In a randomized study of 1311 CHC patients given only Peg-IFN + RBV, Hadziyannis et al reported an SVR of approximately 80% in those infected with genotype 2 or 3 virus versus approximately 52% in those with genotype 1 virus. Several other studies[22-38] of CHC patients with genotype 2 or 3 virus, treated with either Peg-IFN or IFN, both administered with RBV, are summarized in Table 1 and show no better results with either IFN, when given in combination with RBV, for genotypes 2 and 3 viruses.
Notwithstanding the published clinical data[19-38] summarized in Table 1, the debate on the optimal duration of Peg-IFN treatment with RBV continues. In a recent paper, Shiffman et al have suggested that it may be prudent to treat CHC patients with genotype 2 or 3 virus for 24 wk as opposed to 16 wk, to ensure a lower percentage of relapses. The concept of an early virological response, sometimes referred to as a rapid viral response (RVR), reported in some fraction of CHC patients within 4 wk, has been proposed as a clinically useful predictor of SVR. However, while this concept is valuable in CHC patients infected with genotype 1 or 4 virus, some 97% of patients with genotypes 2 and 3 viruses show an RVR, and therefore, this concept is less useful in CHC patients infected with genotype 2 or 3. Importantly, the rates of relapse can increase with therapies of shorter duration, although the SVR rates (27.8% and 58.8%) were inexplicably low in one particular study of genotype 3 CHC patients in Pakistan.
Emerging data[27,30,32,38-40] suggest differences in SVR between patients with genotype 2 or 3 HCV, with genotype 2 yielding better responses than 3. There may also be additional nuances between genotypes 2a and 2c that could be used to the benefit of patients with these sub-types of HCV infection.
NEWER SUPPLEMENTAL TREATMENT OPTIONS TO INCREASE THERAPEUTIC EFFICACY AND PREVENT RELAPSE
Two new adjuvants to existing therapies with IFN + RBV or Peg-IFN + RBV are noteworthy in their potential to vastly improve SVR and clinical outcomes, and importantly, to decrease relapse rates in CHC patients. While abnormalities in glucose metabolism in CHC patients were recognized as far back as 1994, the application of this knowledge in the clinical setting has been introduced in just the past few years, as the epidemic of obesity and pre-diabetes or diabetes has come into sharp focus as a matter of great public health concern.
Eighty-two CHC patients with genotype 2 or 3 virus were treated with IFN + RBV or Peg-IFN + RBV. Insulin resistance was measured by the homeostasis model (HOMA-IR). Patients with HOMA-IR values < 2 had an SVR of 94%, those with HOMA-IR values of 2-4 or > 4 had an SVR of 65%. The authors concluded that SVR rates > 90% are achievable in persons with low HOMA-IR values in genotype 2 and 3 patients, but drop to the 60% level more typically seen in CHC genotype 1 patients when their HOMA-IR values are > 2. Similar results have been reported more recently by others[43-46].
In an elegant series of papers from the Siddiqui Laboratory at the University of California at San Diego, in vitro studies on the mechanisms of HCV-induced changes in liver cells have identified the importance of intracellular calcium and oxidative stress in activating signal transducer and activator of transcription and nuclear factor-kB which in turn, contribute to the release of pro-inflammatory cytokines and contribute to liver pathology in HCV-infected cells[47-51]. This mechanism has been confirmed by others[52,53] and summarized in a recent review, in the context of immune system derangements observed in CHC.
We are in the early stages of designing a pilot study to evaluate the effectiveness of drugs, such as exenatide, used to overcome insulin resistance and agents that would block calcium derangements in the liver of CHC patients infected with HCV genotype 2 or 3.
Published and unpublished clinical observations suggest that an SVR is achieved in 70%-88% of CHC patients infected with genotype 2 or 3 HCV treated with IFN + RBV. A weight-of-evidence analysis using the data cited in Table 1, suggests no greater benefit in treating genotype 2 or 3 infections with Peg-IFN, which can be as much as six to 30 times more expensive than IFN (unpublished data). While the number of patients studied (Table 1) may be smaller than optimally required for a definitive answer to the issue of whether Peg-IFN, despite its additional costs, brings any clinical benefit to CHC patients with genotype 2 or 3 infection, the similarities in SVR between the two IFNs suggest that neither offers a measurable clinical benefit over the other when administered with RBV.
The 2002 National Institutes of Health (NIH) Consensus Conference Statement on Management of Hepatitis C stated, “Among patients with genotypes 2 or 3, SVRs with standard interferon and ribavarin were comparable to those with pegylated interferon and ribavarin, and thus standard interferon and ribavarin could be used in treating patients with those genotypes”. The published data since the 2002 NIH Consensus Statement have not falsified this recommendation. Thus, the recommendation of duration of Peg-IFN therapy for hepatitis C with these genotypes needs to be tempered by whether or not Peg-IFN offers any clinical advantage, given its much higher cost, when used with RBV, and especially in less-developed countries.
1 Weiss U. Hepatitis C. Nature 2005; 436: 929 DOI
2 Malik IA, Ahmad N, Luqman M, Legters LJ, Khalil-Ullah, Zaheeruddin, Ahmed A, Bukhtiari N, Nabi S, Mubarik A. Hepatitis
C as a cause of chronic liver disease in northern Pakistan. J Pak Med Assoc 1992; 42: 67-68 PubMed
3 Aslam M, Aslam J. Seroprevalence of the antibody to hepatitis C in select groups in the Punjab region of Pakistan. J Clin
4 Khan TS, Rizvi F, Rashid A. Hepatitis C seropositivity among chronic liver disease patients in Hazara, Pakistan. J Ayub
Med Coll Abbottabad 2003; 15: 53-55 PubMed
5 Khokhar N, Gill ML, Malik GJ. General seroprevalence of hepatitis C and hepatitis B virus infections in population. J Coll
Physicians Surg Pak 2004; 14: 534-536 PubMed
6 Muhammad N, Jan MA. Frequency of hepatitis "C" in Buner, NWFP. J Coll Physicians Surg Pak 2005; 15: 11-14 PubMed
7 Ahmad N, Asgher M, Shafique M, Qureshi JA. An evidence of high prevalence of Hepatitis C virus in Faisalabad,
Pakistan. Saudi Med J 2007; 28: 390-395 PubMed
8 Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol 2007; 13: 2436-2441 PubMed
9 Chaudhuri S, Das S, Chowdhury A, Santra A, Bhattacharya SK, Naik TN. Molecular epidemiology of HCV infection
10 Hissar SS, Goyal A, Kumar M, Pandey C, Suneetha PV, Sood A, Midha V, Sakhuja P, Malhotra V, Sarin SK. Hepatitis C
virus genotype 3 predominates in North and Central India and is associated with significant histopathologic liver disease.
11 Svirtlih N, Delic D, Simonovic J, Jevtovic D, Dokic L, Gvozdenovic E, Boricic I, Terzic D, Pavic S, Neskovic G, Zerjav S,
Urban V. Hepatitis C virus genotypes in Serbia and Montenegro: the prevalence and clinical significance. World J
Gastroenterol 2007; 13: 355-360 PubMed
12 Sartori M, Andorno S, Avogadro E, Ballare M, La Terra G, Leone F, Quaglia V, Fortina G, Aglietta M. High prevalence of
hepatitis C virus (HCV) genotype 2 in Italian patients with chronic liver disease. Ital J Gastroenterol 1996; 28: 452-456
13 Re V, Lampe E, Yoshida CF, de Oliveira JM, Lewis-Ximinez L, Spinsanti L, Elbarcha O, Contigiani M. Hepatitis C virus
genotypes in Cordoba, Argentina. Unexpected high prevalence of genotype 2. Medicina (B Aires) 2003; 63: 205-210
14 Bassit L, Ribeiro-Dos-Santos G, Da Silva LC, Takei K, Villaca P, David-Neto E, Chamone D, Saez-Alquezar A. Genotype
15 Patel K, McHutchison JG. Initial treatment for chronic hepatitis C: current therapies and their optimal dosing and
duration. Cleve Clin J Med 2004; 71 Suppl 3: S8-S12 PubMed
16 Saleem N, Mubarik A, Qureshi AH, Siddiq M, Ahmad M, Afzal S, Hussain AB, Hashmi SN. Is there a correlation between
degree of viremia and liver histology in chronic hepatitis C? J Pak Med Assoc 2004; 54: 476-479 PubMed
17 Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E, O'Grady J, Reichen J, Diago M, Lin A, Hoffman J,
18 Lindsay KL, Trepo C, Heintges T, Shiffman ML, Gordon SC, Hoefs JC, Schiff ER, Goodman ZD, Laughlin M, Yao R,
Albrecht JK. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial
19 Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht
JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic
20 Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D,
Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med
21 Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H Jr, Bernstein D,
Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM. Peginterferon-alpha2a and ribavirin combination therapy in chronic
hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346-355 PubMed
22 McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK.
Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis
23 Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, Shiffman ML, Zeuzem S, Craxi A, Ling MH, Albrecht J.
Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International
24 Khokhar N. Effectiveness of 48 weeks Interferon alfa-2b in combination with ribavirin as initial treatment of chronic
hepatitis. J Ayub Med Coll Abbottabad 2002; 14: 5-8 PubMed
25 Muhammad N, Jan MA, Rahman N. Outcome of combined interferon-ribavirin in the treatment of chronic hepatitis C. J
Coll Physicians Surg Pak 2004; 14: 651-653 PubMed
26 Hazari S, Panda SK, Gupta SD, Batra Y, Singh R, Acharya SK. Treatment of hepatitis C virus infection in patients of
27 Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, Vinelli F, Scotto G, Bacca D, Annese M, Romano M,
Zechini F, Sogari F, Spirito F, Andriulli A. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3.
28 Medeiros-Filho JE, de Carvalho Mello IM, Pinho JR, Neumann AU, de Mello Malta F, da Silva LC, Carrilho FJ. Differences
in viral kinetics between genotypes 1 and 3 of hepatitis C virus and between cirrhotic and non-cirrhotic patients during
antiviral therapy. World J Gastroenterol 2006; 12: 7271-7277 PubMed
29 Gupta R, Ramakrishna CH, Lakhtakia S, Tandan M, Banerjee R, Reddy DN. Efficacy of low dose peginterferon alpha-2b
with ribavirin on chronic hepatitis C. World J Gastroenterol 2006; 12: 5554-5556 PubMed
30 Elefsiniotis IS, Pantazis KD, Dimitroulopoulos D, Koutsounas S, Moulakakis A, Paraskevas E. Impact of shorter duration
of treatment on virological response rate in genotype 2 or 3 chronic hepatitis C virus infection. Indian J Gastroenterol
2007; 26: 209-213 PubMed
31 Jacobson IM, Brown RS Jr, Freilich B, Afdhal N, Kwo PY, Santoro J, Becker S, Wakil AE, Pound D, Godofsky E, Strauss
R, Bernstein D, Flamm S, Pauly MP, Mukhopadhyay P, Griffel LH, Brass CA. Peginterferon alfa-2b and weight-based or
32 Borroni G, Andreoletti M, Casiraghi MA, Ceriani R, Guerzoni P, Omazzi B, Terreni N, Salerno F. Effectiveness of
pegylated interferon/ribavirin combination in 'real world' patients with chronic hepatitis C virus infection. Aliment
Pharmacol Ther 2008; 27: 790-797 PubMed
33 Rumi MG, Aghemo A, D'Ambrosio R, Ronchi G, Del Ninno E, Gallus S, Colombo M. Lack of rapid virological response
predicts interferon-alpha2b/ribavirin therapy failure in HCV genotype 2 patients: a single-centre study. Antivir Ther 2007;
12: 1033-1040 PubMed
34 Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Sola R, Shafran SD, Barange K, Lin A, Soman A, Zeuzem S.
Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357: 124-134
35 Dalgard O, Bjoro K, Ring-Larsen H, Bjornsson E, Holberg-Petersen M, Skovlund E, Reichard O, Myrvang B, Sundelof B,
Ritland S, Hellum K, Fryden A, Florholmen J, Verbaan H. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in
patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology 2008; 47: 35-42 PubMed
36 Poustchi H, Negro F, Hui J, Cua IH, Brandt LR, Kench JG, George J. Insulin resistance and response to therapy in
37 Kawamura Y, Arase Y, Ikeda K, Suzuki F, Suzuki Y, Kobayashi M, Akuta N, Hosaka T, Sezaki H, Yatsuji H, Kobayashi M,
Kumada H. The efficacy of short-term interferon-beta therapy for chronic hepatitis C patients with low virus load. Intern
38 Ferenci P, Brunner H, Laferl H, Scherzer TM, Maieron A, Strasser M, Fischer G, Hofer H, Bischof M, Stauber R,
Gschwantler M, Steindl-Munda P, Staufer K, Loschenberger K. A randomized, prospective trial of ribavirin 400 mg/day
versus 800 mg/day in combination with peginterferon alfa-2a in hepatitis C virus genotypes 2 and 3. Hepatology 2008;
39 Yu ML, Dai CY, Huang JF, Hou NJ, Lee LP, Hsieh MY, Chiu CF, Lin ZY, Chen SC, Hsieh MY, Wang LY, Chang WY, Chuang
WL. A randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic
40 Berg T, Carosi G. Optimizing outcomes in patients with hepatitis C virus genotype 2 or 3. Antivir Ther 2008; 13 Suppl 1:
41 Zuberi BF, Zuberi FF, Memon SA, Qureshi MH, Ali SZ, Afsar S. Sustained virological response based on rapid virological
response in genotype-3 chronic hepatitis C treated with standard interferon in the Pakistani population. World J
42 Ishigami Y, Kanda T, Wada M, Shimizu Y. [Glucose intolerance during interferon therapy in patients with chronic
hepatitis type C] Nippon Rinsho 1994; 52: 1901-1904 PubMed
43 Simo R, Lecube A, Genesca J, Esteban JI, Hernandez C. Sustained virological response correlates with reduction in the
incidence of glucose abnormalities in patients with chronic hepatitis C virus infection. Diabetes Care 2006; 29: 2462-
44 Imazeki F, Yokosuka O, Fukai K, Kanda T, Kojima H, Saisho H. Prevalence of diabetes mellitus and insulin resistance in
patients with chronic hepatitis C: comparison with hepatitis B virus-infected and hepatitis C virus-cleared patients. Liver
Int 2008; 28: 355-362 PubMed
45 Harrison SA. Insulin resistance among patients with chronic hepatitis C: etiology and impact on treatment. Clin
46 Romero-Gomez M, Fernandez-Rodriguez CM, Andrade RJ, Diago M, Alonso S, Planas R, Sola R, Pons JA, Salmeron J,
Barcena R, Perez R, Carmona I, Duran S. Effect of sustained virological response to treatment on the incidence of
47 Gong G, Waris G, Tanveer R, Siddiqui A. Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces
48 Tardif KD, Waris G, Siddiqui A. Hepatitis C virus, ER stress, and oxidative stress. Trends Microbiol 2005; 13: 159-163
49 Waris G, Turkson J, Hassanein T, Siddiqui A. Hepatitis C virus (HCV) constitutively activates STAT-3 via oxidative stress:
50 Waris G, Felmlee DJ, Negro F, Siddiqui A. Hepatitis C virus induces proteolytic cleavage of sterol regulatory element
51 Nasimuzzaman M, Waris G, Mikolon D, Stupack DG, Siddiqui A. Hepatitis C virus stabilizes hypoxia-inducible factor
52 Farinati F, Cardin R, Bortolami M, Guido M, Rugge M. Oxidative damage, pro-inflammatory cytokines, TGF-alpha and c-
myc in chronic HCV-related hepatitis and cirrhosis. World J Gastroenterol 2006; 12: 2065-2069 PubMed
53 Ogata H, Chinen T, Yoshida T, Kinjyo I, Takaesu G, Shiraishi H, Iida M, Kobayashi T, Yoshimura A. Loss of SOCS3 in the
liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production. Oncogene 2006; 25: 2520-2530 PubMed
54 Mengshol JA, Golden-Mason L, Rosen HR. Mechanisms of Disease: HCV-induced liver injury. Nat Clin Pract
55 NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements 2002; 19: 1-
S- Editor Li LF L- Editor Kerr C E- Editor Lin YP