Korean J Hepatol > Volume 17(1); 2011 > Article
Kim: Durability of a sustained virologic response in patients with chronic hepatitis C treated with peginterferon and ribavirin
A Sustained virologic response is durable in patients with chronic hepatitis C with peginterferon alfa-2a and ribavirin.
Swain MG, Lai MY, Shiffman ML, Cooksley WG, Zeuzem S, Dieterich DT, Abergel A, Pessôa MG, Lin A, Tietz A, Connell EV, Diago M.
Gastroenterology 2010;139(5):1593-1601.
The current standard therapy for chronic hepatitis C virus (HCV) infection is the combination of pegylated interferon and ribavirin. The ultimate goal of treatment in patients with chronic HCV infection is to completely eradicate HCV in infected hosts, and prevent liver-related morbidity and mortality. However, these goals are difficult to measure and it takes long time to assess the achievement of these goals. A sustained virologic response (SVR) has been used as a surrogate marker of these ultimate goals in treatment of chronic hepatitis C. An SVR is defined as undetectable serum HCV RNA at 24 weeks after the end of treatment. To be a useful surrogate marker, achievement of SVR should result in the reduction of liver-related morbidity and mortality, complete eradication of HCV in infected hosts, and no late virologic relapse.
Achievement of SVR has been associated with improvement in liver histology and health-related quality of life, as well as a reduced risk of hepatocellular carcinoma and liver-related mortality.1-3 The survival of patients who achieved SVR was reported to be comparable to that of general population, matched for age and sex.4 However, the development of hepatocellular carcinoma was reported despite achievement of SVR in patients with chronic hepatitis C and advance fibrosis.5
There is some debate as to whether achievement of SVR results in complete eradication of HCV. In a study of 2089 patients with chronic hepatitis C from 3 clinical trials, hepatic HCV RNA was found to correlate with serum HCV RNA in all cases, and 98% of sustained virologic responders had undetectable hepatic HCV RNA.6 Several small studies have described patients who achieved SVR but have residual HCV RNA detected in peripheral blood mononuclear cells with highly sensitive reverse transcription and nested polymerase chain reaction assays.7,8 Whether these findings represent a replication-competent virus or have any clinical significance is unclear.
Several small studies reported SVR achieved with conventional interferon alone or in combination with ribavirin was durable. In these reports, serum HCV RNA remained undetectable in 92-100% of patients who achieved SVR with 2 to 13 years of follow-up.4,5,9-12 However, there are limited data on the durability of SVR achieved with peginterferon in patients with chronic hepatitis C. Swain et al. studied the durability of SVR achieved with peginterferon in 1343 patients.13 They analyzed the durability of SVR in large cohort of patients who were enrolled in one of 9 randomized controlled clinical trials,14-22 which evaluated the efficacy of peginteferon alfa-2a alone or in combination with ribavirin. Total 1343 treatment-naïve patients who achieved SVR and had at least one post-baseline HCV RNA evaluation were assessed. One thousand three hundred thirty one of 1343 patients (99.1%) remained HCV RNA undetectable in serum at mean of 3.9 years after completion of treatment. The durability of SVR in this study was independent of patient characteristics such as HCV mono-infection, HCV-HIV co-infection, or ALT level. The durability of SVR also appeared to be unaffected by the type of treatment. HCV RNA was detected in the serum of 12 patients who obtained SVR in their original studies at mean of 666 days after completing treatment. Among the 12 patients with reappearance of HCV RNA, there were no baseline or treatment factors associated with reappearance of HCV RNA including HCV genotype, sex, age, race, risk factor for infection, or baseline viral load. It was unknown whether these cases reflect relapse or re-infection because of the paucity of paired samples. The findings of this study were comparable with those reported from smaller studies with conventional interferon.
There was one domestic report on the durability of interferon-based therapy in patients with chronic hepatitis C.23 In this study, 73 patients who achieved SVR with conventional interferon or peginterferon in combination with ribavirin were included. HCV RNA reappeared in 8 of 73 (11%), but persistent viremia remained only in one patient (1.4%). Transient positive tests probably represent false-positive test, and the durability of SVR in Korean patients with chronic hepatitis C appears to be similar with those reported in other studies.
In conclusion, this study showed SVR achieved with peginterferon alfa-2a alone or in combination with ribavirin is durable in 99% of patients for at least 4 years after completion of therapy and is independent of patient or treatment characteristics.

Abbreviations

HCV
hepatitis C virus
SVR
sustained virologic response

REFERENCES

1. Berenguer J, Alvarez-Pellicer J, Martín PM, López-Aldeguer J, Von-Wichmann MA, Quereda C, et al. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology 2009;50:407-413. 19575364.
crossref pmid
2. Cammà C, Di Bona D, Schepis F, Heathcote EJ, Zeuzem S, Pockros PJ, et al. Effect of peginterferon alfa-2a on liver histology in chronic hepatitis C: a meta-analysis of individual patient data. Hepatology 2004;39:333-342. 14767986.
crossref pmid
3. George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann J, Di Bisceglie AM. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology 2009;49:729-738. 19072828.
crossref pmid pmc
4. Veldt BJ, Saracco G, Boyer N, Cammà C, Bellobuono A, Hopf U, et al. Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy. Gut 2004;53:1504-1508. 15361504.
crossref pmid pmc
5. Tsuda N, Yuki N, Mochizuki K, Nagaoka T, Yamashiro M, Omura M, et al. Long-term clinical and virological outcomes of chronic hepatitis C after successful interferon therapy. J Med Virol 2004;74:406-413. 15368524.
crossref pmid
6. McHutchison JG, Poynard T, Esteban-Mur R, Davis GL, Goodman ZD, Harvey J, et al. Hepatic HCV RNA before and after treatment with interferon alone or combined with ribavirin. Hepatology 2002;35:688-693. 11870385.
crossref pmid
7. Pham TN, MacParland SA, Mulrooney PM, Cooksley H, Naoumov NV, Michalak TI. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virol 2004;78:5867-5874. 15140984.
crossref pmid pmc
8. Radkowski M, Gallegos-Orozco JF, Jablonska J, Colby TV, Walewska-Zielecka B, Kubicka J, et al. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology 2005;41:106-114. 15619235.
crossref pmid
9. Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997;127:875-881. 9382365.
crossref pmid
10. Formann E, Steindl-Munda P, Hofer H, Jessner W, Bergholz U, Gurguta C, et al. Long-term follow-up of chronic hepatitis C patients with sustained virological response to various forms of interferon-based anti-viral therapy. Aliment Pharmacol Ther 2006;23:507-511. 16441471.
crossref pmid
11. Desmond CP, Roberts SK, Dudley F, Mitchell J, Day C, Nguyen S, et al. Sustained virological response rates and durability of the response to interferon-based therapies in hepatitis C patients treated in the clinical setting. J Viral Hepat 2006;13:311-315. 16637861.
crossref pmid
12. Larghi A, Tagger A, Crosignani A, Ribero ML, Bruno S, Portera G, et al. Clinical significance of hepatic HCV RNA in patients with chronic hepatitis C demonstrating long-term sustained response to interferon-alpha therapy. J Med Virol 1998;55:7-11. 9580879.
crossref pmid
13. Swain MG, Lai MY, Shiffman ML, Cooksley WG, Zeuzem S, Dieterich DT, et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010;139:1593-1601. 20637202.
crossref pmid
14. 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;347:975-982. 12324553.
crossref pmid
15. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. 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. 14996676.
crossref pmid
16. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-García J, Lazzarin A, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004;351:438-450. 15282351.
crossref pmid
17. Fried MW, Jensen DM, Rodriguez-Torres M, Nyberg LM, Di Bisceglie AM, Morgan TR, et al. Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized study of higher doses of peginterferon alpha-2a and ribavirin. Hepatology 2008;48:1033-1043. 18697207.
crossref pmid
18. Heathcote EJ, Shiffman ML, Cooksley WG, Dusheiko GM, Lee SS, Balart L, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343:1673-1680. 11106716.
crossref pmid
19. Pockros PJ, Carithers R, Desmond P, Dhumeaux D, Fried MW, Marcellin P, et al. Efficacy and safety of two-dose regimens of peginterferon alpha-2a compared with interferon alpha-2a in chronic hepatitis C: a multicenter, randomized controlled trial. Am J Gastroenterol 2004;99:1298-1305. 15233669.
crossref pmid
20. Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Solá R, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007;357:124-134. 17625124.
crossref pmid
21. Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343:1666-1672. 11106715.
crossref pmid
22. Zeuzem S, Diago M, Gane E, Reddy KR, Pockros P, Prati D, et al. Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels. Gastroenterology 2004;127:1724-1732. 15578510.
crossref pmid
23. Kim CH, Park BD, Lee JW, Kim YS, Jeong S, Lee DH, et al. Durability of a sustained virologic response in combination therapy with interferon/peginterferon and ribavirin for chronic hepatitis C. Korean J Hepatol 2009;15:70-79. 19346787.
crossref pmid

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