interleukin 28B genetic polymorphism and hepatitis B virus infection

interleukin(iL)28B genetic polymorphism is significantly associated with the sustained virological response rate in patients with chronic hepatitis C treated with pegylated interferon-α(PEG-iFN)plus ribavirin and with spontaneous hepatitis C virus clearance.However,a consensus on the relationship between iL28B genetic polymorphism and the favorable outcome of chronic hepatitis B virus infection defined by hepatitis B e antigen seroconversion,and/or hepatitis B surface antigen seroclearance in patients treated with interferon or PEG-iFN has not been reached.Several reports failed to show a positive association,while some studies demonstrated a positive association in certain subject settings.More prospective studies including large cohorts are needed to determine the possible association between iL28B genetic polymorphism and the outcome of interferon or PEG-iFN treatment for chronic hepatitis B.     

Genetic polymorphism in cyclooxygenase-2 promoter affects hepatic inflammation and fibrosis in patients with chronic hepatitis C

Summary. Cyclooxygenase (COX)-2 is involved in inflammation, anti-apoptosis and carcinogenesis. The -1195GG genotype of single nucleotide polymorphism (SNP) in COX-2 promoter was associated with low platelet counts in patients with chronic hepatitis C. Polymorphism of patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene (rs738409 C>G) have been reported to be associated with cirrhosis, and the major genotype of SNPs near interleukin (IL)28B are related to viral clearance. The present study was designed to assess the contribution of these SNPs to disease progression in patients with chronic hepatitis C. The study enrolled 220 Japanese patients with chronic hepatitis C. Three SNPs, -1195 COX-2, PNPLA3 and IL28B (rs8099917), were genotyped in order to analyze their association with hepatic fibrosis and inflammation. The -1195GG genotype in COX-2 was associated with advanced fibrosis and higher levels of inflammation in the liver tissues. The major genotype of IL28B was also associated with advanced fibrosis, but the polymorphism of PNPLA3 was neither associated with fibrosis nor inflammation. Multivariate analysis showed that -1195GG in COX-2 is an independent factor associated with advanced fibrosis, while the major genotype of IL28B and HCV genotype 2 were other independent factors. In conclusion, the -1195GG genotype in COX-2 is a genetic marker for liver disease progression, while the PNPLA3 genotypes are not associated with disease progression in Japanese patients with chronic hepatitis C.     

Interleukin 28B polymorphisms are the only common genetic variants associated with low-density lipoprotein cholesterol (LDL-C) in genotype-1 chronic hepatitis C and determine the association between LDL-C and treatment response

Low-density lipoprotein cholesterol (LDL-C) levels and interleukin 28B (IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B has been linked with LDL-C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL-C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome-wide association study and developed multivariable predictive models of SVR. IL28B polymorphisms were the only common genetic variants associated with pretreatment LDL-C level in Caucasians (rs12980275, P = 4.7 × 10(-17), poor response IL28B variants associated with lower LDL-C). The association was dependent on HCV infection, IL28B genotype was no longer associated with LDL-C in SVR patients after treatment, while the association remained significant in non-SVR patients (P < 0.001). LDL-C was significantly associated with SVR for heterozygous IL28B genotype patients (P < 0.001) but not for homozygous genotypes. SVR modelling suggested that IL28B heterozygotes with LDL-C > 130 mg/dL and HCV RNA ≤600 000 IU/mL may anticipate cure rates >80%, while the absence of these two criteria was associated with an SVR rate of <35%. IL28B polymorphisms are the only common genetic variants associated with pretreatment LDL-C in G1-HCV. LDL-C remains significantly associated with SVR for heterozygous IL28B genotype patients, where LDL-C and HCV RNA burden may identify those patients with high or low likelihood of cure with pegIFN/RBV therapy.     

Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection

Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related). CONCLUSION: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection.     

IL28B single nucleotide polymorphisms in the treatment of hepatitis C

Recent genome-wide association studies (GWAS) have identified genetic variations near the IL28B gene which are strongly associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. Protective IL28B variations are strongly associated with on-treatment viral kinetics and approximately 2-fold increased sustained virologic response (SVR) rates in HCV genotype 1 and 4 patients. In HCV genotype 1 patients, IL28B variations were shown to be the strongest pre-treatment predictor of virologic response. In the treatment of HCV genotype 2 and 3 infected patients, IL28B variations play only a minor role. Preliminary data indicate that IL28B variations are also associated with treatment outcome of regimens, including directly acting antiviral (DAA) agents, though their impact seems to be attenuated compared to standard treatment. Here, we review these important findings and discuss possible implications for clinical decision making in the treatment of HCV infection.     

Distribution of IL28B Genotypes in Iranian Patients with Chronic Hepatitis C and Healthy Individuals

Background

IL28B polymorphism is recognized as one of the most prominent predictors of hepatitis C spontaneous and treatment-induced clearance. Interestingly, the favorable genotypes of IL28B are found to be more frequent in Asian ethnicity than Caucasian and African populations, respectively. A few studies reported that there is a mysterious association between the IL28B polymorphism and the hepatitis C virus (HCV) genotype in patients with chronic hepatitis C but they did not give any reason for this phenomenon.

Objectives

The foremost purpose of this study was to compare the distribution of IL28B genotypes between Iranian healthy individuals and patients with chronic hepatitis C.

Patients and Methods

In this study, 921 patients with chronic hepatitis C and 142 healthy individuals were included. The IL28B rs12979860 and rs8099917 polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

Results

The frequency of IL28B rs12979860 CC, CT, and TT genotypes in chronic hepatitis C patients was 38%, 48.8%, and 13.2% and in healthy individuals was 43.7%, 48.6%, and 7.7%. Also, the frequency of IL28B rs8099917 TT, GT, and GG genotypes in chronic hepatitis C patients was 58.3%, 37.1%, and 4.6% and in healthy individuals was 64.1%, 32.4% and 3.5%. The differences in the distribution of IL28B rs12979860 and rs8099917 genotypes between patients with chronic hepatitis C and healthy individuals were not statistically significant. When we compared the distribution of IL28B genotypes between the healthy group and the HCV infected patients by HCV genotype, we found 9.8% higher frequency of rs12979860 CC genotype in the healthy individuals than HCV genotype 1 infected patients (P = 0.03) however there was no significant difference in the distribution of rs12979860 genotypes between the healthy and HCV genotype 3 infected groups (P = 0.46).

Conclusions

It seems that the impact of IL28B polymorphism on the spontaneous clearance of HCV genotype 1 is more prominent than HCV genotype 3 which results in the observation of higher rs12979860 C allele frequency in chronic hepatitis C patients with HCV genotype 3 than HCV genotype 1.     

Clinical impact of HFE mutations in Japanese patients with chronic hepatitis C

Background and Aim: HFE mutations, a common cause of hereditary hemochromatosis (HH), are reportedly associated with hepatic iron overload, severe liver fibrosis, and good response to interferon treatment in European patients with chronic hepatitis C (CHC). HH shows ethnicity‐based differences and little is known about the effects of HH mutations on CHC in the Japanese. Thus, the aim of this study was to clarify the clinical influence of HFE mutations in Japanese CHC patients. Methods: In a total of 251 patients with CHC, we analyzed the frequencies of H63D and S65C mutations in the HFE gene, and the influence of these mutations on clinical parameters and response to pegylated‐interferon‐alpha 2b (PEG‐IFN) plus ribavirin therapy. Results: Fourteen patients (5.6%) carried the H63D mutation; all were heterozygotes. No S65C mutations were found. Only hemoglobin levels in the H63D heterozygotes were higher than in wild‐type patients. Eleven of 14 H63D heterozygotes achieved sustained virological response (SVR). On univariate analysis, factors associated with SVR were interleukin 28B (IL28B) polymorphism, age, hepatitis C virus (HCV) genotype, HCV viral load, white blood cell count, stage of fibrosis and H63D mutation. All patients with both TT genotype in IL28B (rs8099917) and H63D mutation in HFE (n = 10) achieved SVR. Conclusions: The H63D mutation has little impact on the clinical characteristics of CHC, but is related to favorable response to PEG‐IFN plus ribavirin therapy, particularly in patients with the TT allele in IL28B.     

Dysregulation of innate immunity in hepatitis C virus genotype 1 IL28B-unfavorable genotype patients: impaired viral kinetics and therapeutic response

Recent studies have shown that a single-nucleotide polymorphism upstream of the interleukin-28B (IL28B) gene plays a major role in predicting therapeutic response in hepatitis C virus (HCV)-infected patients treated with pegylated interferon (PEG-IFN)/ribavirin. We sought to investigate the mechanism of the IL28B polymorphism, specifically as it relates to early HCV viral kinetics, IFN pharmacokinetics, IFN pharmacodynamics, and gene expression profiles. Two prospective cohorts (human immunodeficiency virus [HIV]/HCV-coinfected and HCV-monoinfected) completing treatment with IFN/ribavirin were enrolled. Patients were genotyped at the polymorphic site rs12979860. In the HIV/HCV cohort, frequent serum sampling was completed for HCV RNA and IFN levels. DNA microarray of peripheral blood mononuclear cells and individual expression of IFN-stimulated genes (ISGs) were quantified on IFN therapy. The IL28B-favorable (CC) genotype was associated with improved therapeutic response compared with unfavorable (CT or TT) genotypes. Patients with a favorable genotype had greater first- and second-phase viral kinetics (P = 0.004 and P = 0.036, respectively), IFN maximum antiviral efficiency (P = 0.007) and infected cell death loss (P = 0.009) compared with unfavorable genotypes. Functional annotation analysis of DNA microarray data was consistent with depressed innate immune function, particularly of natural killer cells, from patients with unfavorable genotypes (P <0.004). Induction of innate immunity genes was also lower in unfavorable genotypes. ISG expression at baseline and induction with IFN was independent of IL28B genotype. CONCLUSION: Carriers of the IL28B-favorable genotype were more likely to have superior innate immune response to IFN therapy compared with unfavorable genotypes, suggesting that the unfavorable genotype has aberrant baseline induction of innate immune response pathways resulting in impaired virologic response. IL28B genotype is associated with more rapid viral kinetics and improved treatment response outcomes independent of ISG expression.     

Host factors determining the efficacy of hepatitis C treatment

Combination therapy with pegylated interferon and ribavirin is the standard of care (SOC) for the treatment of chronic hepatitis C (CHC). Treating CHC with SOC may show a sustained virological response (SVR) in approximately 50–70 % of genotype 1 CHC patients and an SVR in 70–90 % of genotype 2 CHC patients. The genotype, baseline viral load, and viral kinetics (i.e., rapid virologic response and early virologic response) can be used as predictors of response-guided therapy. Nonetheless, host factors, e.g. age, ethnicity, insulin resistance, and genetic variations, may also play important roles in the SVR in CHC patients treated with SOC. Recent genome-wide association studies have demonstrated that single-nucleotide polymorphisms near the interleukin 28B gene (IL28B) were associated with SVR to treatment with SOC in CHC patients. The IL28B polymorphisms may contribute to the viral kinetics during treatment. Asian people have favorable IL28B polymorphisms. This factor may at least partly explain the high eradication rate of hepatitis C by SOC in Asia. Combination therapy with direct-acting antivirals (DAAs) and SOC can increase the SVR rates both in treatment-naïve and treatment-experienced patients. Although the IL28B polymorphisms also affect the SVR of triple therapy with SOC and first-generation protease inhibitors, pilot studies have demonstrated that potent DAAs might overcome the influence of IL28B polymorphisms. Thus, the treatment of hepatitis C virus infection could be simplified in the near future.     

Genes and hepatitis C: susceptibility,fibrosis progression and response to treatment

Hepatitis C virus contact and infection show three different phenotypes: spontaneous viral clearance (SVC), chronic hepatitis C (CHC) and sustained virological response (SVR) following antiviral treatment. Many factors, including genetics, influence the evolution of these three phenotypes. We performed a literature search (PubMed) up to 31 January 2010 without language restriction to identify relevant studies on genes and hepatitis C. Additional studies were sought by reviewing the reference lists of the identified articles. Meta‐analysis (using Meta‐disk 1.4) was conducted to evaluate the association of single nucleotide polymorphism (SNP) in the IL28B region and SVR. The candidate gene approach showed strong relationships between human leucocyte antigen class II (DQB1^*0301 and DRB1^*1101) and SVC. A cirrhosis risk score involving 7 SNPs has been validated recently. The set of odds ratios of studies demonstrated an association between SNP (rs12987960/rs8099917) in the IL28B and SVR in CHC treated with peginterferon plus ribavirin (OR: 4.6; 95% CI: 2.9–7.3). The overall distribution of protective allele correlated with ethnic differences in SVR (Asians, Europeans, Hispanic and Afro‐Americans) together with SVC, but not with fibrosis stage or viral load. These polymorphisms did not influence SVR in very‐easy‐to‐treat patients such as genotype 2/3, rapid virological responders or patients with acute hepatitis C. While the genetic fingerprint for fibrosis progression remains elusive, IL28b polymorphism predicts SVC and SVR. However, nearly half of patients achieving SVR did not show favourable genotype. Further genetic signals are warranted to complete the puzzle of factors influencing hepatitis C.     

IL28B genomic-based treatment paradigms for patients with chronic hepatitis C infection: the future of personalized HCV therapies

Genome-wide association studies (GWAS) have recently identified host genetic variation to be critical for predicting treatment response and spontaneous clearance in patients infected with hepatitis C virus (HCV). These important new studies are reviewed and their future clinical implications discussed. Single-nucleotide polymorphisms in the region of the IL28B gene on chromosome 19, coding for the interferon (IFN)-λ-3 or IL28B gene, are strongly associated with treatment response to pegylated IFN and ribavirin in patients infected with genotype 1 HCV. The good response variant is associated with a twofold increase in the rate of cure. Allele frequencies differ between ethnic groups, largely explaining the observed differences in response rates between Caucasians, African Americans and Asians. IL28B polymorphism is also strongly associated with spontaneous clearance of HCV. The biological mechanisms responsible for these genetic associations remain unknown and are the focus of ongoing research. Knowledge of a patient's IL28B genotype is likely to aid in clinical decision making with standard of care regimens. Future studies will investigate the possibility of individualizing treatment duration and novel regimens according to IL28B type.     

IL28B polymorphisms associated with therapy response in Chilean chronic hepatitis C patients

AIM:To analyze the association of three IL28B single nucleotide polymorphisms with response to therapy in Chilean patients infected with hepatitis C virus CV.METHODS:We studied two groups of patients with chronic CV infection genotype 1,under standard combined treatment with pegylated interferon plus ribavirin.One group consisted of 50 patients with sustained virological response,whereas the second group consisted of 49 null responders.In order to analyze the IL28B single nucleotide polymorphisms rs12979860...     

Duration of peginterferon therapy in acute hepatitis C: a randomized trial

Spontaneous resolution of acute hepatitis C virus infection cannot be predicted, and chronic evolution of the disease occurs in a majority of cases. To assess the efficacy and safety of peginterferon alpha-2b administered for 8, 12, or 24 weeks in patients with acute hepatitis C virus infection a total of 161 patients were identified with acute hepatitis C virus infection. Of these, 30 patients refused treatment but were retained in the study as a nonrandomized comparison group. Of the 131 patients who consented to treatment, 29 patients spontaneously resolved, leaving 102 patients randomly assigned to peginterferon alpha-2b (1.5 microg/kg) for 8 weeks (group A; n=34), 12 weeks (group B; n=34), and 24 weeks (group C; n=34). The primary end point was sustained virologic response. An intent-to-treat analysis was used for efficacy and safety end points. Sustained virologic response was achieved in 23/34 (67.6%), 28/34 (82.4%), and 31/34 (91.2%) of patients in groups A, B, and C, respectively; all had undetectable hepatitis C virus RNA 48 weeks after the end of therapy. Treatment for 8 or 12 weeks was effective in genotypes 2, 3, and 4, whereas genotype 1 required 24 weeks of therapy. The 8- and 12-week regimens were associated with fewer adverse events compared with the 24-week regimen. In conclusion, peginterferon alpha-2b effectively induces high sustained virologic response rates in patients with acute hepatitis C virus infection, thus preventing development of chronic hepatitis C. Duration of treatment should be further optimized based on genotype and rapid virologic response at week 4.     

Factors responsible for the discrepancy between IL28B polymorphism prediction and the viral response to peginterferon plus ribavirin therapy in Japanese chronic hepatitis C patients

Aim: IL28B polymorphisms serve to predict response to pegylated interferon plus ribavirin therapy (PEG IFN/RBV) in Japanese patients with chronic hepatitis C (CHC) very reliably. However, the prediction by the IL28B polymorphism contradicted the virological response to PEG IFN/RBV in some patients. Here, we aimed to investigate the factors responsible for the discrepancy between the IL28B polymorphism prediction and virological responses. Methods: CHC patients with genotype 1b and high viral load were enrolled in this study. In a case-control study, clinical and virological factors were analyzed for 130 patients with rs8099917 TT genotype and 96 patients with rs8099917 TG or GG genotype who were matched according to sex, age, hemoglobin level and platelet count. Results: Higher low-density lipoprotein (LDL) cholesterol, lower γ-glutamyltransferase and the percentage of wild-type phenotype at amino acids 70 and 91 were significantly associated with the rs8099917 TT genotype. Multivariate analysis showed that rs8099917 TG or GG genotype, older age and lower LDL cholesterol were independently associated with the non-virological responder (NVR) phenotype. In patients with rs8099917 TT genotype (predicted as virological responder [VR]), multivariate analysis showed that older age was independently associated with NVR. In patients with rs8099917 TG or GG genotype (predicted as NVR), multivariate analysis showed that younger age was independently associated with VR. Conclusion: Patient age gave rise to the discrepancy between the prediction by IL28B polymorphism and the virological responses, suggesting that patients should be treated at a younger age.     

Different distributions of hepatitis C virus genotypes among HIV-infected patients with acute and chronic hepatitis C according to interleukin-28B genotype

Objectives

The C allele of the single nucleotide polymorphism rs12979860, located near the interleukin‐28B (IL‐28B) gene, has a strong impact on hepatitis C virus (HCV) treatment response, as well as on spontaneous viral clearance. In patients with chronic hepatitis C (CHC), genotype CC carriers harbour HCV genotype 3 more commonly than those with non‐CC genotypes. The aim of this study was to compare the HCV genotype distributions, according to IL‐28B genotype, in HIV‐infected patients with CHC and those with acute hepatitis C (AHC).

Methods

The rs12979860 genotype was determined by polymerase chain reaction (PCR) in two subpopulations of HIV‐infected patients. The first consisted of 80 German patients with AHC. The second consisted of 476 patients with CHC, belonging to one German and two Spanish cohorts.

Results

In the AHC group, 31 (81.6%) rs12979860 CC carriers were infected with HCV genotype 1 or 4 vs. 32 (76.2%) among non‐CC carriers (P=0.948). In patients with CHC, among those with the CC genotype, 119 (54.6%) were infected with HCV genotype 1 or 4 and 99 (45.4%) with genotype 2 or 3, whereas in the subset with non‐CC genotypes, 200 (77.5%) harboured HCV genotype 1 or 4 and 58 (22.5%) genotype 2 or 3 (P<0.001).

Conclusions

Among HIV‐infected patients with CHC, those bearing the IL‐28B genotype CC were more commonly infected with genotype 3 than subjects with non‐CC genotypes, whereas in HIV‐infected subjects with AHC this finding was not obtained. These results strongly suggest that the protective effect of the CC genotype against evolution to CHC is mainly exerted in patients infected with HCV genotype 1 or 4.     

Spontaneous clearance of hepatitis C infection after liver transplantation from IL28B rs12979860 CC donors

Genetic polymorphisms adjacent to IL28B have been previously associated with spontaneous clearance of hepatitis C virus (HCV) and a higher rate of sustained virological response to interferon-based treatment in HCV genotype 1-infected patients. A recent study has shown that patients with the CC genotype of the rs12979860 single nucleotide polymorphism upstream from the IL28B gene are more likely to clear HCV spontaneously relative to the CT or TT genotype. In the liver transplant cohort, HCV recurs almost universally in patients with detectable HCV RNA at the time of transplantation. The spontaneous clearance of HCV infection after transplant is very rare. We report two cases of spontaneous clearance of HCV genotype 1 infection after liver transplantation from homozygous IL28B CC donors. This finding may be explained by alterations in the host immune responses to HCV after transplantation with a CC donor liver, which has potential implications for donor selection in HCV-positive recipients.     

Interferon-λ-related genes and therapeutic response in Chinese hepatitis C patients

AIM: To determine the association between rapid viral response and IL28 B, IL28 RA, IL10 RB and Mx A polymorphisms in the Chinese Han population.METHODS: The study cohort consisted of 238 chronic hepatitis C patients treated with interferon(IFN)-α-2b and ribavirin. Six single nucleotide polymorphisms were genotyped using the ABI Taq Man allelic discrimination assay. Biochemical indices were measured at baseline. Serum hepatitis C virus(HCV) RNA was detected at weeks 0, 4, 12 and 24 of therapy.RESULTS: Only IL28 B rs12980275 was associated with treatment response in the Chinese Han population. Patients carrying AG/GG genotypes had a reduced rapid viral response compared with patients carrying the AA genotype(additive model: adjusted OR = 0.43, 95%CI: 0.24-0.75). It took less time for patients with the AA genotype to achieve a viral load 500 copies/m L(logrank test, P = 0.004). In addition, the protective effect of genotype AA was independent of baseline viral load. HCV genotype, and baseline white blood cell count, α-fetoprotein and viral load might also help predict treatment response. The area under the receiveroperating characteristic curve was 0.726. CONCLUSION: IL28 B rs12980275 AA genotype is a strong predictor of positive response to IFN therapy in Chinese Han patients with hepatitis C.     

Role of IL28B and inosine triphosphatase polymorphisms in the treatment of chronic hepatitis C virus genotype 6 infection

IL28B and inosine triphosphatase (ITPA) polymorphisms are able to predict treatment response and degree of ribavirin‐related anaemia, respectively, in the treatment of chronic hepatitis C virus (HCV) infection. However, their roles in the treatment of chronic HCV genotype 6 remain undetermined. Sixty patients who were infected with HCV genotype 6 were commenced on 48 weeks of combination pegylated interferon and ribavirin therapy. Response to therapy, profiles of haemoglobin changes and platelet counts during therapy and their associations with IL28B rs8099917 and ITPA rs1127354 polymorphisms were analysed. The overall sustained virologic response (SVR) rate was 91.7%. 18 patients (30.0%) required a reduction in ribavirin dosage. The distribution of IL28B rs8099917 TT/TG genotypes and ITPA rs1127354 CC/CA genotypes were in Hardy–Weinberg equilibrium. IL28B rs8099917 TT genotype, when compared to TG genotype, was significantly associated with an increased SVR rate (96.2% and 62.5%, respectively) and was the only clinical parameter that predicted SVR (P = 0.014). The same significant association was observed when analysing allelic frequencies (T vs G, P = 0.001). ITPA rs1127354 CA genotype, when compared to CC genotype, was associated with lesser degree of anaemia throughout therapy (P < 0.05 for all time points). ITPA polymorphisms showed no association with changes in platelet count throughout therapy (P > 0.05 for all time points) and was not associated with SVR (P = 0.640). In chronic HCV genotype 6 infection, IL28B polymorphisms were associated with response to therapy. ITPA polymorphisms influenced the degree of anaemia but not thrombocytopenia during therapy.     

Thrombocytopenia in pegylated interferon and ribavirin combination therapy for chronic hepatitis C

Background

This study aimed to examine the therapeutic effect and prognostic indicators of pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy in thrombocytopenic patients with chronic hepatitis C, hepatitis C virus (HCV)-related cirrhosis, and those who underwent splenectomy or partial splenic embolization (PSE).

Methods

Of 326 patients with HCV-related chronic liver disease (252 with genotype 1b and 74 with genotype 2a/2b) treated with PEG-IFN/RBV, 90 were diagnosed with cirrhosis.

Results

Regardless of the degree of thrombocytopenia, the administration rate was significantly higher in the splenectomy/PSE group compared to the cirrhosis group. However, in patients with genotype 1b, the sustained virological response (SVR) rate was significantly lower in the cirrhosis and the splenectomy/PSE groups compared to the chronic hepatitis group. No cirrhotic patients with platelets less than 80,000 achieved an SVR. Patients with genotype 2a/2b were more likely to achieve an SVR than genotype 1b. Prognostic factors for SVR in patients with genotype 1b included the absence of esophageal and gastric varices, high serum ALT, low AST/ALT ratio, and the major homo type of the IL28B gene. Splenectomy- or PSE-facilitated induction of IFN in patients with genotype 2a/2b was more likely to achieve an SVR by an IFN dose maintenance regimen. Patients with genotype 1b have a low SVR regardless of splenectomy/PSE. In particular, patients with a hetero/minor type of IL28B did not have an SVR.

Conclusions

Splenectomy/PSE for IFN therapy should be performed in patients expected to achieve a treatment response, considering their genotype and IL28B.