J Med Virol. 2014 Aug;86(8):1360-5.

Hepatitis C virus genotypes circulating in chronic hepatitis C patients in Thailand and their responses to combined PEG-IFN and RBV therapy.                                                                        

Kumthip K, Chusri P, Pantip C, Thongsawat S, O’Brien A, Nelson KE, Maneekarn N.

Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand

 

Supplement

Hepatitis C virus (HCV) is now classified into seven major genotypes with several closely related subtypes. Different HCV genotypes and subtypes are distributed in different parts of the world. Genotypes 1-3 are widely distributed throughout the world; genotypes 1 and 2 are endemic in West Africa while genotype 3 is endemic in India. Genotypes 4 and 5 are prevalent in Africa and genotype 6 in Southeast Asia. In 1998-2000, the prevalence of HCV genotypes 1, 3, and 6 detected in Thai blood donors have been reported ranging from 25.7% to 27.8%, 36.7% to 39.6%, and 29.4% to 31%, respectively [1]. Our study investigated the prevalence of HCV genotypes in chronic hepatitis C patients who visited Chiang Mai University Hospital, Chiang Mai, Thailand during 2003-2010 and found that three major HCV genotypes 1, 3, and 6 remained currently circulating in this area at the prevalent rate of 31%, 54.5%, and 14.5%, respectively (Table 1). Subtype 3a is the most common HCV subtype found in Thailand.

Previous studies have shown repeatedly that HCV genotypes 2 and 3 showed a better response to IFN-a based treatment (78–86%) than genotype 1 (42–52%). However, the data of HCV genotype 6 on the response to treatment is limited. Taking advantage of HCV genotype diversity detected in our patients, we investigated the response of different HCV genotypes to PEG-IFN and ribavirin therapy. Patients infected chronically with HCV were treated with PEG-IFN/ribavirin based on the standard regimens for each HCV genotype and followed up the patients until the end of treatment and 6 months afterward. The patients were classified into three groups based on the presence of viral RNA at the end of treatment and 6 months after completion of treatment as shown in Figure 1 [2]. It was found that the sustained virological response rates for genotypes 1, 3, and 6 were 73.5%, 80.2%, and 69.5%, respectively (Table 1). Interestingly, our findings revealed that subtype 6f exhibited higher degree of resistance to PEG-IFN/ribavirin treatment than genotypes 1 and 3.

It has been demonstrated that viral factor particular genotype of the virus is one of the most important factors contributed to different levels of the response to IFN treatment. In agreement with other group of investigators, our group have shown that mutations in several regions in the HCV genome such as NS3 and NS5A of subtypes 1a, 1b, and 6f significantly correlated with the response to PEG-IFN/ribavirin therapy [2,3]. In addition to analysis of mutation in HCV genome, we have assessed mechanism of HCV mediated-IFN resistance. We have further demonstrated that NS5A protein of HCV inhibits IFN activity by blocking IFN signaling pathway and that NS5A of HCV genotype 1 exhibits stronger inhibitory effects on IFN signaling than does genotype 3 NS5A protein [4]. These observations provide new insights into the mechanisms by which HCV NS5A proteins from different genotypes influence IFN signaling and may account for genotype-related differences in IFN treatment responses.

The importance of the study is two-fold. First, it shows recent distribution of HCV genotypes circulating in Thai patients. Various HCV genotypes are detected among chronic hepatitis C patients including genotypes 1a, 1b, 3a, 3b, 6a, 6f, 6i, and 6n. Second, this study shows response rate of different HCV genotypes to PEG-IFN/ribavirin therapy particular genotype 6 which their data are very little documented. We demonstrate that patients infected with genotypes 1 and 6 are more resistant to PEG-IFN and ribavirin therapy than genotype 3 and that subtypes 3b and 6f display high rate of the relapse after completion of the treatment.

 

References

  1. Jutavijittum P, Jiviriyawat Y, Yousukh A, Pantip C, Maneekarn N, Toriyama K. Genotypic distribution of hepatitis C virus in voluntary blood donors of northern Thailand. Southeast Asian J Trop Med Public Health 2009; 40:471–479.
  2. Kumthip K, Pantip C, Chusri P, Thongsawat S, O’Brien A, Nelson KE, Maneekarn N. Correlation between mutations in the core and NS5A genes of hepatitis C virus genotypes 1a, 1b, 3a, 3b, 6f and the response to pegylated interferon and ribavirin combination therapy. J Viral Hepat 2011; 18:e117-125.
  3. Chusri P, Kumthip K, Pantip C, Thongsawat S, O’Brien A, Maneekarn N. Influence of amino acid variations in the NS3, NS4A and NS4B of HCV genotypes 1a, 1b, 3a, 3b and 6f on the response to pegylated interferon and ribavirin combination therapy. Virus Res 2015; 196: 37-43.
  4. Kumthip K, Chusri P, Jilg N, Zhao L, Fusco DN, Zhao H, Goto K, Cheng D, Schaefer EA, Zhang L, Pantip C, Thongsawat S, O’Brien A, Peng LF, Maneekarn N, Chung RT, Lin W. Hepatitis C virus NS5A disrupts STAT1 phosphorylation and suppresses type I interferon signaling. J Virol 2012; 86(16): 8581-8591.

 

 

Table 1. PEG-IFN and ribavirin therapy and rate of response in chronic hepatitis C patients

NM tab

 

 

Maneekarn fig1

Figure 1. Virologic response to PEG-IFN and ribavirin therapy

Patient’s sera were collected before, during, at the end of treatment and at 6 months after end of treatment. The pretreatment sera were tested for HCV viral load and genotype to assign duration of treatment. The sera collected at the end of treatment and at 6 months afterwards were tested for the presence of viral RNA to classify the types of response to the PEG-IFN and ribavirin therapy which are responder, nonresponder, and relapser.

 

 

 

Contact

Niwat Maneekarn, D.V.M., Ph.D.

Professor

Dept. of Microbiology, Faculty of Medicine, Chiang Mai University

Chiang Mai 50200, Thailand

Email: nmaneeka@med.cmu.ac.th

Telephone: +6653945332

Fax: +6653217144

 

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