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PERSPECTIVAS TERAPEUTICAS PARA EL TRATAMIENTO DE LA HEPATITIS C CRONICA

PERSPECTIVAS TERAPEUTICAS PARA EL TRATAMIENTO DE LA HEPATITIS C CRONICA

(especial para SIIC © Derechos reservados)
La mayoría de las nuevas moléculas analizadas en este artículo deberán ser estudiadas más a fondo, quizás asociadas con los interferones pegilados y la ribavirina, para determinar su valor real, especialmente en lo que respecta a criterios de valoración clínicos, como la respuesta viral sostenida y los puntajes de fibrosis hepática.
aspinall9.jpg Autor:
Richard Aspinall
Columnista Experto de SIIC

Institución:
Division of Gastroenterology/Hepatology, Scripps Clinic


Artículos publicados por Richard Aspinall
Coautor
Paul Pockros* 
MD, Scripps Clinic*
Recepción del artículo
30 de Diciembre, 2005
Aprobación
13 de Enero, 2006
Primera edición
22 de Junio, 2006
Segunda edición, ampliada y corregida
7 de Junio, 2021

Resumen
Los ensayos clínicos recientes mostraron que el tratamiento combinado con interferón pegilado y ribavirina puede lograr una respuesta viral sostenida en la mayoría de los pacientes con hepatitis C crónica que califiquen para dicha terapia. Sin embargo, debido a que muchos pacientes no pueden ser tratados (o escogen no serlo en virtud de los efectos colaterales), se hace muy necesario mejorar la eficacia y disminuir los efectos adversos de los fármacos empleados. Los nuevos fármacos recién diseñados ofrecen la ventaja de ser más selectivos y existen varias moléculas prometedoras en fases avanzadas de investigación. En este artículo se revisarán los descubrimientos más recientes que hacen al tratamiento inmunomodulador para la hepatitis C crónica, incluidas las interleuquinas, timosina, interferón gamma, moléculas semejantes al interferón, inhibidores de la inosina 5'-monofosfato deshidrogenasa, antagonistas del factor de necrosis tumoral, análogos de la ribavirina, inhibidores de la caspasa y las vacunas terapéuticas. Si bien algunos de estos compuestos no probaron ser eficaces, muchos se encuentran en las fases preliminares de investigación y se los considera agentes terapéuticos potencialmente efectivos.

Palabras clave
hepatitis C, inmunomoduladores, interleuquina, IMPDH, viramidina


Artículo completo

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Abstract
Recent clinical trials have shown that combination therapy with pegylated interferon and ribavirin can achieve a sustained virological response in the majority of patients with chronic hepatitis C who qualify for treatment. However, because many patients are unable to be treated (or choose not to due to side effects), there remains a pressing need for improving efficacy and reducing adverse effects. Newer drugs emerging from the laboratory offer hopes of more rational drug targeting and there are several promising pharmaceuticals in the advanced stages of development. In this article we review recent developments in novel immunomodulatory therapies for chronic hepatitis C, including interleukins, thymosin, interferon gamma, oral-interferon-like molecules, IMPDH inhibitors, tumor necrosis factor antagonists, ribavirin analogues, caspase inhibitors and therapeutic vaccines. Although some of these compounds have failed to show benefit, many are still in the early stages of development and therefore hold out promise as potentially effective new therapies.

Key words
hepatitis C, immunomodulators, interleukin, IMPDH, viramidine


Full text
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Clasificación en siicsalud
Artículos originales > Expertos del Mundo >
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Especialidades
Principal: Farmacología, Medicina Interna
Relacionadas: Gastroenterología, Infectología, Inmunología



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Enviar correspondencia a:
Paul Pockros, Division of Gastroenterology/Hepatology, Scripps Clinic, CA 92037, 10666 North Torrey Pines Road, La Jolla, EE.UU.
Bibliografía del artículo
1. Thimme R, Bukh J, Spangenberg HC, et al. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci USA 2002; 99:15661-8.
2. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005; 5:215-29.
3. Strader DB, Wright T, Thomas DL, Seeff LB. AASLD practice guideline: Diagnosis, management, and treatment of hepatitis C. Hepatology 2004; 39:1147-71.
4. Alberti A, Benvegnu L. Management of hepatitis C. J Hepatol 2003; 38 Suppl 1:S104-18.
5. Manns MP, McHutchison JG, Gordon SC et al. Peg-interferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomized trial. Lancet 2001; 358:958-965.
6. Hadziyannis SJ, Sette H, Morgan TR, et al. Peginterferon-a2a and ribavirin combination therapy in chronic hepatitis C. Ann Intern Med 2004; 140:346-355.
7. Aspinall RJ, Pockros PJ. The management of side-effects during therapy for hepatitis C. Aliment Pharmacol Ther 2004; 20:917-29.
8. Shiffman ML, Di Bisceglie AM, Lindsay KL, et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004; 126:1015-23.
9. Zhong J, Gastaminza P, Cheng G, et al. Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci USA 2005; 102:9294-9.
10. Lindenbach BD, Evans MJ, Syder AJ, et al. Complete Replication of hepatitis C virus in cell culture. Science 2005 Jun 9; [Epub ahead of print].
11. Wakita T, Pietschmann T, Kato T, et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 2005 Jun 12; [Epub ahead of print].
12. Trinchieri G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 1995; 13:251-76.
13. Gately MK, Renzetti LM, Magram J, et al. The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol 1998; 16:495-521.
14. Rossol S, Marinos G, Carucci P, et al. Interleukin-12 induction of Th1 cytokines is important for viral clearance in chronic hepatitis B. J Clin Invest 1997; 99:3025-33.
15. Kanto T, Hayashi N, Takehara T, et al. Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals. J Immunol 1999; 162:5584-91.
16. Tsubouchi E, Akbar SM, Murakami H, et al. Isolation and functional analysis of circulating dendritic cells from hepatitis C virus (HCV) RNA-positive and HCV RNA-negative patients with chronic hepatitis C: role of antiviral therapy. Clin Exp Immunol 2004; 137:417-23.
17. Eisen-Vandervelde AL, Waggoner SN, Yao et al. Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation. J Biol Chem 2004; 279:43479-86.
18. Schlaak JF, Pitz T, Lohr HF, et al. Interleukin 12 enhances deficient HCV-antigen-induced Th1-type immune response of peripheral blood mononuclear cells. J Med Virol 1998; 56:112-7.
19. O'Brien CB, Moonka DK, Henzel BS, et al. A pilot trial of recombinant interleukin-12 in patients with chronic hepatitis C who previously failed treatment with interferon-alpha. Am J Gastroenterol 2001; 96:2473-9.
20. Pockros PJ, Patel K, O'Brien C, et al. A multicenter study of recombinant human interleukin 12 for the treatment of chronic hepatitis C virus infection in patients nonresponsive to previous therapy. Hepatology 2003; 37:1368-74.
21. Zeuzem S, Hopf U, Carreno V, et al. A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis C. Hepatology 1999; 29:1280-7.
22. McHutchison JG, Giannelli G, Nyberg L, et al. A pilot study of daily subcutaneous interleukin-10 in patients with chronic hepatitis C infection. J Interferon Cytokine Res 1999;19:1265-70.
23. Nelson DR, Lauwers GY, Lau JY, Davis GL. Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders. Gastroenterology 2000; 118:655-60.
24. Nelson DR, Tu Z, Soldevila-Pico C, et al. Long-term interleukin 10 therapy in chronic hepatitis C patients has a proviral and anti-inflammatory effect. Hepatology 2003; 38:859-68.
25. Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, et al. Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. J Clin Invest 2000; 106:1239-49.
26. Francavilla V, Accapezzato D, De Salvo M, et al. Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms. Eur J Immunol 2004; 34:427-37.
27. Pardo M, Castillo I, Oliva H, et al. A pilot study of recombinant interleukin-2 for treatment of chronic hepatitis C. Hepatology 1997; 26:1318-21.
28. Hengge UR, Roggendorf M, Goos M. Lack of significant viral load alterations of hepatitis B virus and hepatitis C virus during treatment with IL-2 and highly active antiretroviral therapy. AIDS 2000; 14:2617-9.
29. Thibault V, Delaugerre C, Calvez V, et al. Interleukin 2 treatment does not modify hepatitis B or C replication in human immunodeficiency virus-infected patients: results from a randomized control trial. Hepatology 2002; 35:238-9.
30. Serrate SA, Schulof RS, Leondaridis L, et al. Modulation of human natural killer cell cytotoxic activity, lymphokine production, and interleukin 2 receptor expression by thymic hormones. J Immunol 1987; 139:2338-43.
31. Rasi G, DiVirgilio D, Mutchnick MG et al. Combination thymosin alpha 1 and lymphoblastoid interferon treatment in chronic hepatitis C. Gut 1996; 39:679-683.
32. Sherman KE, Sjogren M, Creager RL et al. Combination therapy with thymosin alpha 1 and interferon for the treatment of chronic hepatitis C infection: a randomized, placebo-controlled, double-blind trial. Hepatology 1998; 27:1128-1135.
33. Rustgi V. Combination therapy of thymalfasin (thymosin-alpha 1) and peginterferon alfa-2a in patients with chronic hepatitis C virus infection who are non-responders to standard treatment. Journal of Gastroenterology and Hepatology 2004; 19(S6):S76-S78.
34. Farrar MA, Schreiber RD. The molecular cell biology of inteferon-gamma and its receptor. Annu Rev Immunol 1993; 11:571-611.
35. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol 1997; 15:749-795.
36. Pinzani M, Marra F. Cytokine receptors and signaling in hepatic stellate cells. Semin Liver Dis 2001; 21:397-416.
37. Tsuruoka N, Sugiyama M, Tawaragi Y, et al. Inhibition of in vitro angiogenesis by lymphotoxin and interferon-gamma. Biochem Biophys Res Commun 1988; 155:429-35.
38. Cheney IW, Lai VC, Zhong W, et al. Comparative analysis of anti-hepatitis C virus activity and gene expression mediated by alpha, beta, and gamma interferons. J Virol 2002; 76:11148-54.
39. Soza A, Heller T, Ghany M, et al. Pilot study of interferon gamma for chronic hepatitis C. J Hepatol 2005; 43:67-71.
40. Muir AJ, Sylvestre PB, Rockey DC. Interferon gamma-1b for the treatment of chronic hepatitis C infection. Gastroenterology 2003; 124 (Suppl 1):A718.
41. Pockros PJ, Jeffers L, Afdhal N, et al. Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of IFN gamma-1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis. Gastroenterology 2005; 128(4: suppl 2):A715.
42. Dockrell DH, Kinghorn GR. Imiquimod and resiquimod as novel immunomodulators. J Antimicrob Chemother 2001; 48:751-5.
43. Pockros PJ, Tong M, Wright T et al. A phase IIa placebo-controlled, double blind trial to determine the safety, tolerability, PK/PD of an oral interferon inducer, resiquimod, in chronic HCV. Gastroenterology 2003; 124 (Suppl 1):A766.
44. Horsmans Y, Berg T, Desager JP, et al. Isatoribine, a toll-like receptor 7 agonist, significantly reduced plasma viral load in a clinical proof-of-concept study in patients with chronic hepatitis C virus infection. Hepatology 2004; 40(suppl 1):282A-283A.
45. Tilg H, Vogel W, Dinarello CA. Interferon-alpha induces circulating tumor necrosis factor receptor p55 in humans. Blood 1995; 85:433-5.
46. Zein NN; Etanercept Study Group. Etanercept as an adjuvant to interferon and ribavirin in treatment-naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double-blind, placebo-controlled study. J Hepatol 2005; 42:315-22.
47. Lau JY, Tam RC, Liang TJ, et al. Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology 2002; 35:1002-9.
48. Zhou S, Liu R, Baroudy BM, et al. The effect of ribavirin and IMPDH inhibitors on hepatitis C virus subgenomic replicon RNA. Virology 2003; 310:333-42.
49. McHutchison JG, Cheung R, Shiffman M, al el. A 4-week trial of VX497 (an IMPDH inhibitor) combined with interferon in previously untreated patients with chronic hepatitis C. Hepatology 2001; 34(suppl):329A.
50. Zha J, Garg V, McNair L, et al. Pharmacokinetic-pharmacodynamic relationships of merimepodib and ribavirin in pegylated interferon-alfa/ribavirin/merimepodib treated genotype-1 HCV patients non-responsive to previous therapy with interferon-alfa/ribavirin. Hepatology 2004; 40 (suppl 1):250A.
51. Cornberg M, Hinrichsen H, Teuber G, et al. Mycophenolate mofetil in combination with recombinant interferon alfa-2a in interferon-nonresponder patients with chronic hepatitis C. J Hepatol 2002; 37:843-7.
52. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347:975-82.
53. Watson J. Prospects for hepatitis C virus therapeutics: Levovirin and Viramidine as improved derivatives of ribavirin. Curr Opin Investig Drugs 2002; 3:680-683.
54. Pockros PJ, Pessoa MG, Diago M, et al. Combination of levovirin (LVV) and peginterferon alfa-2a (40 kd) (Pegasys®) fails to generate a virological response comparable to ribavirin (RBV, Copegus®) and peginterferon alfa-2a (40kd) in patients with chronic hepatitis C. Hepatology 2004; 40(suppl 1):391A.
55. Lin CC, Lourenco D, Xu G, Yeh LT. Disposition and metabolic profiles of [14C]viramidine and [14C]ribavirin in rat and monkey red blood cells and liver. Antimicrob Agents Chemother 2004; 48:1872-5.
56. Gish RG, Nelson D, Arora S et al. Virologic and safety outcomes in therapy-naïve patients treated for chronic hepatitis C with viramidine in combination with pegylated interferon alfa-2a. Gastroenterology 2005; 128(4 suppl 2):A681.
57. Natori S, Higuchi H, Contreras P, Gores GJ. The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury. Liver Transpl 2003; 9:278-84.
58. Pockros P, Schiff E, Shiffman M, et al. The first caspase inhibitor, IDN-6556, given orally lowers liver enzymes in HCV patients. Hepatology 2003; 38:1326.
59. Hilleman MR. Six decades of vaccine development - a personal history. Nat Med 1998; 4(Suppl 5):507-514.
60. Farci P, Alter HJ, Govindarajan S, et al. Lack of protective immunity against reinfection with hepatitis C virus. Science. 1992; 258:135-140.
61. Bassett SE, Guerra B, Brasky K, et al. Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection. Hepatology 2001; 33:1479-1487.
62. Major ME, Mihalik K, Puig M, et al. Previously infected and recovered chimpanzees exhibit rapid responses that control hepatitis C virus replication upon rechallenge. J Virol 2002; 76:6586-6595.
63. Nevens F, Roskams T, Van Vlierberghe H, et al. A pilot study of therapeutic vaccination with envelope protein E1 in 35 patients with chronic hepatitis C. Hepatology 2003; 38:1289-96.
64. Horsmans Y, Brenard R, Staerkel P, et al. Tolerability and immunogenicity of HCV E1 therapeutic vaccination in patients with chronic hepatitis C on interferon plus ribavirin. J Hepatol 2005; 42(suppl 2):A568.
65. Wedemeyer H, Berg T, Manns MP, et al. Induction of the TH1/TC1 type immunity in chronic hepatitis C non-responder patients with the therapeutic peptide vaccine IC41. J Hepatol 2005; 42(suppl 2):A19.

 
 
 
 
 
 
 
 
 
 
 
 
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