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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2011  |  Volume : 54  |  Issue : 1  |  Page : 81-84
The sustained virologic response of nonresponder hepatitis C virus patients with retreatment


1 Kocaeli Univaersity Medical Faculty, Infectious Diseases anc Clinical Microbiology, Kocaeli, Turkey
2 Polymerase Chain Reaction Unit, Kocaeli, Turkey

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Date of Web Publication7-Mar-2011
 

   Abstract 

Background: Pegylated interferon and ribavirin combination therapy remain the first-line treatment for chronic hepatitis C virus (HCV) infection. In contrast to the large number of studies in treatment-naive patients, the effectiveness of retreatment in patients who have previously failed pegylated interferon based therapy is not much reported. Objectives: The aim of this retrospective study was to focus on the efficacy of pegylated interferon alpha and ribavirin in retreated chronic hepatitis C patients. Patients and Methods: All patients were treated with pegylated interferon alpha either 2a (180 μg) or 2b (1.5μg/kg) subcutaneously once weekly for a 48-week period, plus ribavirin 1000-1200 mg/day. The patient who had a negative HCV RNA at the end of 48 weeks were followed up for 24 weeks, and the patients who relapsed in the post-treatment follow-up period of 24 weeks were treated again with pegylated interferon alpha; but if the first treatment was administered with pegylated interferon alpha 2a, the second was administered with pegylated interferon alpha 2b and if pegylated interferon alpha 2b, then the second with pegylated interferon alpha 2a. Results: We evaluated the outcome of our patients with chronic HCV who achieved a viral response at the end of the therapy, but did not achive sustained virologic response; 54% (38/70) of patients did achieve sustained virologic response, while 46% (32/70) of patients did not (eight patients did not achieve early virologic response, five patients were nonresponders at 24th week of the treatment, the remaining 19 patient had negative HCV at the end of the therapy but did not achieve sustained virologic response). We began from 19 patients to 8 patients, who had negative HCV RNA at the end of the treatment, but did not achieve sustained virologic response, interferon plus ribavirin therapy again. If the patient had interferon alpha 2a, we gave in the second tour alpha 2b; and if alpha 2b, then alpha 2a. The early virologic response of these nine patients were found to be 63% (5/8). These 5 patients who had rapid virologic response and early virologic response at the second therapy achieved sustained virologic response this time. Conclusions: These findings suggest that the standard 48-week treatment is insufficient and that an extended course of treatment may be necessary. Relapse is a poorly understood clinical outcome in the treatment of chronic HCV patients. Retreament can give a chance to some patients specially who have early virologic response and negative HCV RNA at the end of the first therapy.

Keywords: Hepatitis C virus, pegylated interferon, retreatment

How to cite this article:
Akhan SC, Gurel E, Sayan M. The sustained virologic response of nonresponder hepatitis C virus patients with retreatment. Indian J Pathol Microbiol 2011;54:81-4

How to cite this URL:
Akhan SC, Gurel E, Sayan M. The sustained virologic response of nonresponder hepatitis C virus patients with retreatment. Indian J Pathol Microbiol [serial online] 2011 [cited 2019 Dec 8];54:81-4. Available from: http://www.ijpmonline.org/text.asp?2011/54/1/81/77330



   Introduction Top


Pegylated interferon and ribavirin combination therapy remain the first-line treatment for chronic hepatitis C virus (HCV) infection. [1],[2] In contrast to the large number of studies in treatment-naive patients, the effectiveness of retreatment in patients who have previously failed pegylated interferon based therapy is not much reported. The aim of this retrospective study was to focus on the efficacy of pegylated interferon alpha and ribavirin in retreated chronic hepatitis C patients. The primary treatment goal is eradication of the virus. This is defined as the absence of HCV RNA after 6 months of antiviral treatment completion (sustained virologic response).


   Patients and Methods Top


Of the anti-HCV positive 197 patients who were admitted to the Infectious Diseases and Clinical Microbiology policlinic from January 2004 to December 2007, 127 were candidates for therapy. We evaluated the sustained virologic response of 70 (29 female, 41 male) patients. The treatment for the remaining 57 patients has commenced but was not taken into consideration because they had not completed their 1-year treatment yet. All the patients were genotype 1 and one patient was genotype 4.

The treatment criteria for all patients were as follows:

  • Anti-HCV positive
  • Detectable HCV-RNA by polymerase chain reaction (PCR) for at least 6 months
  • With liver biopsy plus biochemical parameters indicating chronic hepatitis C
Exclusion criteria were previous treatment with antivirals or steroids, and the presence of signs of cirrhosis, coinfection with HBV, HIV, and abnormal ultrasound findings.

The predictability of a sustained virologic response was based on the rapid virologic response defined at week 4 negative HCV RNA, early virologic response defined at week 12 as an at least 2-log decline from baseline of the HCV RNA level.

Study Design

All patients were treated with pegylated interferon alpha either 2a (180 μg) or 2b (1.5 μg/kg) subcutaneously once weekly for a 48-week period, plus ribavirin 1000-1200 mg/day. The patient who had a negative HCV RNA at the end of 48 weeks were followed up for 24 weeks and the patients who relapsed in the post-treatment follow-up period of 24 weeks were treated again with pegylated interferon alpha, but if the first treatment was administered with pegylated interferon alpha 2a, the second was administered with pegylated interferon alpha 2b and if pegylated interferon alpha 2b, then the second with pegylated interferon alpha 2a. The 13 other patients not responding to treatment after 12 weeks (8 patients) and 24 weeks (5 patients), respectively, were excluded from the retreatment group from different reasons, because 4 patients lost to follow up, 6 refuse the retreatment, and 2 become ineligible (low platelet count and one become lichen planus) for retreatment. Only one patient who has 6 months therapy previosly is on retreatment and he did not complete the re-treatment yet.

Before beginning the therapy, all patients were given a full account of the type of treatment they were going to have, its duration, the expected adverse effects and benefits, as well as alternative treatment options for their disease, and were asked to freely decide on their treatment. Routine serum biochemistry tests included serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), g-glutamyl transpeptidase (GGT), alkaline phosphatase, albumin, globulin, total bilirubin, prothrombin time, and blood cell counts. Anti-HCV antibody was measured by a third-generation commercial ELISA (Innotest HCV Ab IV; Innogenetics NV, Ghent, Belgium). The third generation assay detects antibodies for four viral antigens (CORE, NS3, NS4, and NS5). Liver biopsy was obtained from all patients within 12 months before admission to the study.

Detection of HCV RNA, Genotyping, and Quantitation of HCV RNA

Blood samples were centrifuged immediately, sera/plasma were separated, aliquoted, and then kept at ≤-70°C until testing. HCV RNA was isolated from serum/plasma samples by a biorobot workstation using magnetic - particle technology (NucliSENS, easyMAG, bioMérieux, Boxtel, Holland). Samples were assayed for HCV RNA by reverse transcription (RT) PCR with primers from the most conserved 5'-UTR Serum HCV RNA levels were quantified by using the COBAS AMPLICOR HCV Monitor 2.0 (Roche Diagnostics GmbH, Mannheim, Germany). For each sample and control, the Cobas Amplicor Analyzer (Roche Diagnostics GmbH, Mannheim, Germany) automatically determined the HCV RNA titer, between 6.0E+2 and 5.0E+5 IU/mL. The HCV strain was determined by RT-PCR amplification of the genome followed by sequencing for genotyping of the strain. Genotyping was carried out by using freshly isolated RNA. The RNA was reverse transcribed with random primers and genotyping was done by using type-specific primers based on NS5 region. RT-PCR was carried out under the following conditions: 10 cycles of amplifications at 94°C for 1 min, 61°C for 1 min, 72°C for 1 min, followed by 30 cycles of amplification at 90°C for 0.5 min, 59°C for 1 min, 72°C for 1 min, and final extension at 72°C for 7 min. [3],[4]

Statistical Analysis

Statistical analysis was performed with ANOVA (Repeated Measures Analysis). P values less than 0.05 were considered as statistically significant.


   Results Top


We evaluated the outcome of our patients with chronic HCV who achieved a viral response at the end of the therapy, but did not achive sustained virologic response; 54% (38/70) of patients did achieve sustained virologic response, while 46% (32/70) of patients did not (8 patients did not achieve early virologic response, 5 patients were nonresponders at 24th week of the treatment, the remaining 19 patient had negative HCV at the end of the therapy but did not achieve sustained virologic response). Pegylated interferon was well tolerated in patients but ribavirin needs dose adjustment because of hemoglobin decreases, but not more than 4 weeks. And 36% (25/70) of patients achieved an RVR and EVR; 32 patients were slow responders; 81% (57/70) of patients had negative HCV RNA at the end of the treatment. Lack of response to treatment was defined as failure to achieve an early virologic response by week 12 or presence of detectable HCV RNA at week 24 or after completion of pegylated interferon + ribavirin therapy. We began from 19 patients to 8 patients, who had negative HCV RNA at the end of the treatment, but did not achieve sustained virologic response, interferon plus ribavirin therapy again. If the patient had interferon alpha 2a, we gave in the second tour alpha 2b; and if alpha 2b, then alpha 2a. The early virologic response of these nine patients were found to be 63% (5/8). These five patients who had rapid virologic response and early virologic response at the second therapy achieved SVR this time. An option is the re-treatment with a second course pegylated interferon + ribavirin [Figure 1] [Table 1], [Table 2] and [Table 3]. If we compare HCV RNA and ALT levels of sustained virologic response positive and negative patients there are no statistically significant difference (P=0.002, P=0.029).
Figure 1: Study design and results. RVR: rapid virologic response; EVR: early virologic response; SR: slow responders; SVR: sustained viral response

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Table 1: Median hepatitis C virus RNA levels

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Table 2: Median alanine aminotransferase levels

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Table 3: Comparison of hepatitis C virus RNA and alanine aminotransferase levels before treatment with 3rd, 6th, 12th, and aftre treatment levels

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   Discussion Top


Pegylated interferon and ribavirin combination therapy remain the first-line treatment for chronic HCV infection. Patients who are most likely to respond to re-treatment can be identified at week 12. The chance is bigger if the patient had early virologic response and negative HCV RNA at the first treatment. [5],[6] Currently, there are limited therapeutic options available for patients with chronic HCV whose treatment with pegylated interferon α and ribavirin proves unsuccessful. One approach has been to retreat patients with another course of pegylated interferon and ribavirin. Cheruvattath et al. did not notice any significant benefit in their cohort of patients who were treated with another course of pegylated interferon and ribavirin; the response rate was only 10%. [7] But we do not agree with this opinion, because we had sustained virologic response of five patients with retreatment. Besides genotypes, the response to treatment is often dependent on factors such as adherence, viral load pre-treatment (poor response if viral load is above 2 million copies/mL or 800 000 IU/mL). As shown in [Table 1], pretreatment median HCV RNA titers were found 1 log much more in sustained virologic response negative patients compared to sustained virologic response positive patients. The other reason we achieved in five patients sustained virologic response with retreatment may due to the the patients has milder fibrosis and none of them had cirrhosis. We could not say anything about the shorter disease duration, because as the patient diagnosed with antiHCV positvity, we follow up 6 months and we make liver biopsy and then begin the treatment. HCV patients who fail pegylated interferon plus ribavirin in the first 3 months may represent a highly resistant group of patients who need more effective treatment strategies, preferably with multidrug combinations. Retreatment of the patients, who finished the 48-week therapy and had negative HCV RNA at the end of this therapy, with another course of pegylated interferon plus RBV after they relapsed to an initial course of pegylated interferon plus RBV, is of marginal benefit. Jensen et al. reported that retreatment of nonresponders with pegylated interferon alpha 2b plus ribavirin for 72 weeks significantly increased sustained virologic response rates compared with retreatment for 48 weeks. The overall sustained virologic response rate was low, but patients who are most likely to respond to retreatment can be identified at week 12. [5] A limitation of our study is that it is retrospective. However, to our knowledge, this is the first published report on the experience in changing the pegylated interferon, practice-based setting of retreatment of HCV with pegylated interferon plus ribavirin after failure of an initial course of pegylated interferon and ribavirin. Jacobson et al. reported that retreatment of patients who previously did not attain sustained virologic response with conventional interferon plus ribavirin, retreatment with pegylated interferon alpha 2b plus ribavirin was also an effective treatment approach. In this study, 42% of previous relapsers and 8% of previous nonresponders attained sustained virologic response. [8] We believe that both pegylated interferons may be alternative to each other for options aimed at lack of response. An important point in that study regarding the two patients who did achieve sustained virologic response is that they were treated for >48 weeks. They were treated for a total of 68 and 72 weeks (for 48 weeks after HCV RNA became negative) during the second course of pegylated interferon plus ribavirin. These patients were treated for a longer period of time because they demonstrated fluctuating levels of viremia, including positive HCV RNA following periods of undetectable RNA. Ribavirin dosing is viewed as an important factor in mitigating relapse. For that reason, we tried to give full dose ribavirin (1000-1200 mg/day, 48 weeks) to the patients. Another important factor is rapid virologic response. Patients who attain rapid virologic response potentially have a higher likelihood of attaining sustained virologic response and a lower likelihood of experiencing relapse than patients who have detectable HCV RNA at week 4 because the former experience a longer duration of continuous undetectable HCV RNA than the latter. Failure to attain early virologic response has a negative predictive value and is the basis for the 12-week stopping rule. [9],[10],[11],[12],[13],[14],[15],[16],[17]


   Conclusions Top


These findings suggest that the standard 48-week treatment is insufficient and that an extended course of treatment may be necessary. Relapse is a poorly understood clinical outcome in the treatment of chronic HCV patients. Retreatment can give a chance to some patients specially who have early virologic response and negative HCV RNA at the end of the first therapy.

 
   References Top

1.Yoshida EM, Sherman M, Bain VG, Cooper CL, Deschênes M, Marotta PJ, et al. Re-treatment with peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have relapsed or not responded to a first course of pegylated interferon-based therapy. Can J Gastroenterol 2009;23:180-4.  Back to cited text no. 1
    
2.Gambarin-Gelwan M, Jacobson IM. Optimal dose of peginterferon and ribavirin for treatment of chronic hepatitis C. J Viral Hepat 2008;15:623-33.  Back to cited text no. 2
    
3.Chayama K. Genotyping Hepatitis C Virus by Type Specific Primers for PCR Based on NS5 Region. Totowa, NJ: Humana Press; 1998.  Back to cited text no. 3
    
4.Akhan SC, Kalender B, Ruzgar M. The response to pegylated interferon alpha 2a in haemodialysis patients with hepatitis C virus infection. Infection 2008;36:341-4.  Back to cited text no. 4
    
5.Jensen DM, Marcellin P, Freilich B, Andreone P, Di Bisceglie A, Brandão-Mello CE, et al. Retreatmentof patients with chronic hepatitis C who do not respond to peginterferonalpha2b: A randomized trial. Ann Intern Med 2009;150:528-40.  Back to cited text no. 5
    
6.Angelico M, Koehler-Horst B, Piccolo P, Angelico F, Gentile S, Francioso S, et al. Peginterferon alpha-2a and ribavirin versus peginterferon alpha-2a monotherapy in early virological responders and peginterferon alpha-2a and ribavirin versus peginterferon alpha-2a, ribavirin and amantadine triple therapy in early virological nonresponders: The SMIEC II trial in naïve patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 2008;20:680-7.  Back to cited text no. 6
    
7.Cheruvattath R, Rosati MJ, Gautam M, Vargas HE, Rakela J, Balan V. Pegylated interferon and ribavirin failures: Ýs retreatment an option?. Dig Dis Sci 2007;52:732-6.   Back to cited text no. 7
    
8.Jacobson IM, Gonzalez SA, Ahmed F, Lebovics E, Min AD, Bodenheimer HC Jr, et al. A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C. Am J Gastroenterol 2005;100:2453-62.  Back to cited text no. 8
    
9.Poordad FF, Flamm SL. Virological relapse in chronic hepatitis C. Antivir Ther 2009;14:303-13.  Back to cited text no. 9
    
10.Lee SS, Abdo AA. Predicting antiviral treatment response in chronic hepatitis C: How accurate and how soon?. J Antimicrob Chemother 2003;51:487-91.  Back to cited text no. 10
    
11.Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009;41:1105-9.  Back to cited text no. 11
    
12.Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009;41:1100-4.  Back to cited text no. 12
    
13.Krawitt EL, Ashikaga T, Gordon SR, Ferrentino N, Ray MA, Lidofsky SD. Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C. J Hepatol 2005;43:243-9.  Back to cited text no. 13
    
14.Parise E, Cheinquer H, Crespo D, Meirelles A, Martinelli A, Sette H, et al. Peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) in retreatment of chronic hepatitis C patients, nonresponders and relapsers to previous conventional interferon plus ribavirin therapy. Braz J Infect Dis 2006;10:11-6.  Back to cited text no. 14
    
15.Sherman M, Yoshida EM, Deschenes M, Krajden M, Bain VG, Peltekian K, et al. Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy. Gut 2006;55:1631-8.  Back to cited text no. 15
    
16.Poynard T, Colombo M, Bruix J, Schiff E, Terg R, Flamm S, et al. Peginterferon alfa-2b and ribavirin: Effective in patients with hepatitis C who failed interferon alfa/ribavirin therapy. Gastroenterology 2009;136:1618-28.  Back to cited text no. 16
    
17.Berg C, Goncales FL Jr, Bernstein DE, Sette H Jr, Rasenack J, Diago M, et al. Re-treatment of chronic hepatitis C patients after relapse: Efficacy of peginterferon-alpha-2a (40 kDa) and ribavirin. J Viral Hepat 2006;13:435-40.  Back to cited text no. 17
    

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Correspondence Address:
Sila Cetin Akhan
Kocaeli University Medical Faculty Infectious Diseases and Clinical Microbiology, Kocaeli
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.77330

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