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Revista Española de Enfermedades Digestivas

versión impresa ISSN 1130-0108

Rev. esp. enferm. dig. vol.101 no.10 Madrid oct. 2009

 

EDITORIAL

 

Viral dynamics and prediction of response to treatment with pegylated interferon and ribavirin in patients with chronic hepatitis C

Dinámica viral y predicción de la respuesta al tratamiento con interferón pegilado y ribavirina en pacientes con hepatitis crónica por virus C

 

 

J. Aguilar Reina

Emeritus, Servicio Andaluz de Salud. Hospitales Universitarios Virgen del Rocío. Sevilla, Spain

 

 

Chronic infection with hepatitis C virus (HCV) affects a huge number of people worldwide and may progress to liver cirrhosis and hepatocarcinoma. It is the first cause of liver transplantation in western countries, and results in major healthcare and social costs. Treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV) may modify disease progression if successful in eradicating infection, which only occurs in slightly more than half of patients. The rest, around 40%, will only receive a costly medication that usually impairs quality of life and may at times induce serious adverse events with no benefits whatsoever. Such events increase in number in the presence of concomitant medication including erythropoietin or colony-stimulating factors, which allow initiating or maintaining therapy in cytopenic subjects. A significant number of infected patients who would potentially benefit from therapy remain untreated because of such uncertainty and likely general status worsening long-term, and PEG-IFN + RBV is commonly administered only to subjects with advanced disease, where effectiveness is lower. Such circumstances have encouraged a search for response predictors, either negative or positive.

Male gender, age older than 45 years, and overweight are known to be associated with lower response rates. However, none of these factors, or their simultaneous occurrence, will determine therapy failure; nor their absence accurately predicts therapy success. When other parameters are also considered, including genotype, viral load, body mass index, liver fibrosis extent, alcohol use or iron metabolism, predictive capabilities improve, but a relevant group of patients remains where treatment results in unexpected effects. Only when two extreme groups are considered, with hypothetical cohorts (1) where each and every patient has all favorable or unfavorable parameters (body mass index above 30 kg/m2 or below 20 kg/m2; age older than 60 years or younger than 20; viral load greater than 9,000,000 IU/ml or smaller than 40,000 IU/ml; advanced or absent liver fibrosis; binge or no drinking, abnormal or normal transaminase index), are significant differences observed. However, such hypothetical cohorts are far removed from the real scenarios where treatment decisions are to be made.

The contribution of other parameters requiring biochemical tests unusual in daily practice has been investigated - increased peripheral insulin resistance is associated with lower chances of response to PEG-INF + RBV, but more than 30% of patients with HOMA > 2 will eventually exhibit virus eradication (2). Quasispecies present before treatment onset influence such response (3).

Evidence that a number of host-related factors, in addition to virus-related factors, condition treatment response has prompted genetic studies initially on the major histocompatibility complex (4) and then on numerous genes in a quest for a genetic signature predictive of response (5). Research is ongoing using powerful technologies to broadly analyze the human genome (6).

An analysis of data obtained for the accreditation of therapy with PEG-IFNa2a + RBV was first to provide a factor with a high negative predictive value: when viral load was not negative or had at least decreased by 2 log10 after 12 weeks on treatment (early virological response), a sustained response could only be expected in 3% of treated individuals. Using PEG-IFNa2b + RBV, the odds for response under those same conditions was 0%. The importance of these results is greater, inasmuch as they refer to carriers of viral genotype 1, which induces a lower response rate and requires treatment for 48 weeks. Failure to respond early has led to therapy discontinuation after 3 months in patients who otherwise would have received medication for longer periods of time without ever reaching viral eradication; however, a sustained response cannot be taken for granted in positive cases, and will only be found in around 70% of subjects (7,8).

The study of viral kinetics during therapy allowed to identify a so-called rapid response (when viral load as assessed with a sensitive method is negative after 4 weeks), and also led to predict response at the end of treatment (9-12); it also allowed to variably shorten length of therapy in patients infected with any genotype (13-15), and to suggest prolonged therapy for those infected with genotype 1 in the absence of rapid response (16).

While the identification of such response types - given their negative predictive value - has allowed to reduce discomfort, adverse effects, and costs by discontinuing treatment when advisable, it also served to encourage physicians and patients to improve adherence when there is a response, and to initiate therapy early in order to rapidly have reliable predictive information available. Several studies suggest that decreases in viral load will be identified in association with potential sustained responses in much less than 4 weeks, maybe during the first few days on therapy (17-19). In the current issue of Revista Española de Enfermedades Digestivas, Hernández et al. (20) deal with this issue by researching the relationship between viral load decrease within one month after treatment onset and the possibility of predicting response at therapy completion; they find a high predictive value for rapid response, and also for reductions by 2 by 2 log10 at 2 and 4 weeks, despite the series' limited size. This amount of viral load reduction leads to consider rapid response at weeks 2 and 4, and if the expected response at 3 months ultimately occurs much earlier this will logically identify those who will eventually have their infection eradicated (provided they will complete therapy), even though the negative predictive value becomes necessarily lower, since patients with smaller viral load decreases may later present with early response and then exhibit sustained response. This paper suggests that a viral dynamics approach may offer still more information regarding the prediction of PEG-IFN + RBV effectiveness in patients with chronic infection with HCV.

Sustained response, or a lack thereof, may be considered the result and expression of a number of forces that, on the one hand, facilitate and, on the other hand, oppose virus eradication. Such forces include all the aforementioned factors and them some unknown ones, and essentially refer to viral sensitivity and capacity to block therapy-induced mechanisms and immune response in each specific patient. This interpretation may account for the predictive ability of both early and rapid responses (as an expression of the balance between forces during early treatment), which is higher than that obtained when considering the limited number of factors involved in sustained response.

 

References

1. Foster GR, Fried MW, Hadziyannis SJ, Messinger D, Freivogel K, Weiland O. Prediction of sustained virological response in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) and ribavirin. Scand J Gastroenterol 2007; 42: 247-55.        [ Links ]

2. Romero-Gómez M, del Mar Viloria M, Andrade RJ, Salmerón J, Diago M, Fernández-Rodríguez CM. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology 2005; 128: 636-41.        [ Links ]

3. Salmerón J, de Rueda PM, Ruiz-Extremera A, Casado J, Huertas C, Bernal MC, et al. Quasispecies as predictive response factors for antiviral treatment in patients with chronic hepatitis C. Dig Dis Sci 2006; 51: 960-7.        [ Links ]

4. Romero-Gómez M, González-Escribano MF, Torres B, Barroso N, Montes-Cano MA, Sánchez-Muñoz D, et al. HLA class I B44 is associated with sustained response to interferon + ribavirin therapy in patients with chronic hepatitis C. Am J Gastroenterol 2003; 98: 1621-6.        [ Links ]

5. Asselah T, Bieche I, Narguet S, Sabbagh A, Laurendeau I, Ripault MP, et al. Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 2008; 57: 516-24.        [ Links ]

6. Aurora R, Donlin MJ, Cannon NA, Tavis JE. Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans. J Clin Invest 2009; 119: 225-36.        [ Links ]

7. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL, Jr., et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-82.        [ Links ]

8. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38: 645-52.        [ Links ]

9. Ferenci P. Predicting the therapeutic response in patients with chronic hepatitis C: the role of viral kinetic studies. J Antimicrobial Chemotherapy 2004; 53: 15-8.        [ Links ]

10. Bárcena R, Moreno A, del Campo S, Muriel A, Mateos ML, Garrido E, et al. The magnitude of week 4 HCV RNA decay on pegylated interferon/ribavirin accurately predicts virological failure in patients with genotype 1. Antivir Ther 2007; 12: 401-6.        [ Links ]

11. Jensen DM, Morgan TR, Marcellin P, Pockros PJ, Reddy KR, Hadziyannis SJ, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006; 43: 954-60.        [ Links ]

12. Yu JW, Wang GQ, Sun LJ, Li XG, Li SC. Predictive value of rapid virological response and early virological response on sustained virological response in HCV patients treated with pegylated interferon alpha-2a and ribavirin. J Gastroenterol Hepatol 2007; 22: 832-6.        [ Links ]

13. Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, et al. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005; 352: 2609-17.        [ Links ]

14. Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Gonçales FL, Jr., et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol 2005; 43: 425-33.        [ Links ]

15. Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. Gastroenterology 2006; 131: 451-60.        [ Links ]

16. Sánchez-Tapias JM, Diago M, Escartín P, Enríquez J, Romero-Gómez M, Bárcena R, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006; 131: 451-60.        [ Links ]

17. Layden JE, Layden TJ, Reddy KR, Levy-Drummer RS, Poulakos J, Neumann AU. First phase viral kinetic parameters as predictors of treatment response and their influence on the second phase viral decline. J Viral Hepat 2002; 9: 340-5.        [ Links ]

18. Hsu CS, Liu CJ, Lai MY, Chen PJ, Kao JH, Chen DS. Early viral kinetics during treatment of chronic hepatitis C virus infection with pegylated interferon alpha plus ribavirin in Taiwan. Intervirology 2007; 50: 310-5.        [ Links ]

19. Buti M, Sánchez-Avila F, Lurie Y, Stalgis C, Valdés A, Martell M, et al. Viral kinetics in genotype 1 chronic hepatitis C patients during therapy with 2 different doses of peginterferon alfa-2b plus ribavirin. Hepatology 2002; 35: 930-6.        [ Links ]

20. Hernández A, Domper F, León A, Lorente R, López B, de la Santa E, et al. Viral kenitics during the first month of treatment in patients with genotype 1 chronic hepatitis C. Rev Esp Enferm Dig 2009; 101: 671-9.        [ Links ]

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