Early decline of the HCV core antigen can predict SVR in patients with HCV treated by Pegylated interferon plus ribavirin combination therapy

OBJECTIVE: Pegylated interferon (PEG‐IFN) plus ribavirin (RBV) combination therapy is now a popular treatment for patients with chronic hepatitis C; however, the reported sustained virologic response (SVR) rate remains at nearly 50% in genotype 1b infected patients. Therefore, it is of clinical benefit to be able to predict the effect of combination therapy on individual patients earlier in the treatment. We estimated the predictive serum HCV core antigen levels for SVR in the early therapeutic stage of combination therapy. METHODS: The HCV core antigen in patients with high‐level HCV viremia, in whom standard PEG‐IFNα2b plus RBV combination therapy had been completed, was measured at baseline and at 3, 7, 14, 28 and 84 days of treatment, and their SVR was determined at 24 weeks after treatment. Sixty genotype 1b‐ and 30 genotype 2‐infected patients were included. RESULTS: Thirty (50%) genotype 1b and 27 (90%) genotype 2 patients achieved a SVR. In genotype 1b patients the decline of HCV core antigen levels was statistically different between the SVR and non‐SVR groups. When we defined a separation level at 500 fmol/L, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for SVR at day 7 was 79.4%, 88.5%, 90%, 76.7%, and 83.3%, respectively. In genotype 2 patients, there was no significant difference in the HCV core antigen values between the SVR and non‐SVR groups. CONCLUSION: In genotype 1b patients, 500 fmol/L of HCV core antigen level at day 7 was the best predictor for therapeutic response in the early stage of treatment.     

Quantification of hepatitis C virus in patients treated with peginterferon-alfa 2a plus ribavirin treatment by COBAS TaqMan HCV test

Summary. Extremely low levels of serum hepatitis C virus (HCV) RNA can be detected by COBAS TaqMan HCV test. To investigate whether the COBAS TaqMan HCV test is useful for measuring rapid virological response (RVR) and early virological response (EVR) to predict sustained virological response (SVR), we compared the virological response to PEG‐IFN‐alfa 2a plus RBV in 76 patients infected with HCV genotype 1 when undetectable HCV RNA by the COBAS TaqMan HCV test was used, with those when below 1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test was used, which corresponded to the use of traditional methods. Among the 76 patients, 28 (36.8%) had SVR, 13 (17.1%) relapsed, 19 (25.0%) did not respond, and 16 (21.0%) discontinued the treatment due to side effects. The positive predictive values for SVR based on undetectable HCV RNA by COBAS TaqMan HCV test at 24 weeks after the end of treatment [10/10 (100%) at week 4, 21/23 (91.3%) at week 8 and 26/33 (78.7%) at week 12] were superior to those based on <1.7 log IU/mL HCV RNA [17/19 (89.4%) at week 4, 27/38 (71.0%) at week 8, and 27/43 (62.7%) at week 12]. The negative predictive values for SVR based on <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test [46/57 (80.7%) at week 4, 37/38 (97.3%) at week 8, and 32/33 (96.9%) at week 12] were superior to those based on undetectable HCV RNA [48/66 (72.7%) at week 4, 46/53 (86.7%) at week 8, and 41/43 (95.3%) at week 12]. The utilization of both undetectable RNA and <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test is useful and could predict SVR and non‐SVR patients with greater accuracy.     

Recent approach for diagnosis of early HCV infection

Detection of HCV infection during the window phase of infection, before seroconversion, is important in blood screening. However, a significant delay exists between the time of infection and the development of antibodies. The delay in window period can last up to 70 days. The aim of the present study was to investigate the kinetics of HCV markers during early infection, with detection of HCV core antigen as an early method for diagnosis. The study included determination of HCV RNA by qualitative and quantitative PCR, HCV core antigen detection by enzyme linked immunosorbent assay (ELISA) and specific serological markers including anti-HCV IgG and IgM. The study was carried out on 34 patients diagnosed as non A non B acute hepatitis and proved to be hepatitis C by qualitative HCV RNA PCR. Sixteen healthy control subjects were also included. From each consenting patient and control, blood samples were collected and serum was separated and subjected to determination of AST and ALT and the following virological laboratory tests: HCV core antigen detection by ELISA, determination of specific anti-HCV IgM and specific anti-HCV IgG, qualitative and quantitative determination of HCV RNA by second version of PCR. In patients, the median quantity of HCV RNA was 739.1 x 10(3) lu/ml with minimum quantity 2.1 x 10(3) lu/ml and maximum 38352.3 x 10(3) lu/ml. A comparison between the different diagnostic methods revealed that the highest sensitivity was for HCV-core antigen detection (82.4%), specificity was 100% negative predictive value was 72.2% and positive predictive value was 100%. Specific anti-HCV IgG had moderate levels of sensitivity (58.5%), specificity (75%), negative predictive value (46.2%)and positive predictive value (83.3%). The least sensitive method was the specific anti-HCV IgM (29.4%) with negative predictive value 40% but had specificity and positive predictive value of 100% of each. From this study we could conclude the followings: From virological methods, serological detection of specific IgM anti-HCV had the least sensitivity limits, while it had the highest specificity and positive predictive value. Specific anti-HCV IgG had moderate sensitivity and specificity. The most sensitive and specific tool for diagnosis of early HCV viraemia was the detection of HCV core Ag by ELISA when compared to molecular biological methods.     

Two week induction of interferon‐beta followed by pegylated interferon alpha‐2b and ribavirin for chronic infection with hepatitis C

Objectives: To elucidate the efficacy of interferon (IFN)‐beta induction therapy followed by pegylated IFN alpha and ribavirin for chronic infection with hepatitis C virus (HCV). Methods: Patients chronically infected with HCV genotype 1, high titer were enrolled. Twice daily bolus injections of 3 million units IFN‐beta were administered for 14 days. Thereafter, weekly injection of pegylated IFN alpha 2b and daily intake of ribavirin were followed. Therapy duration was adjusted according to the response to the therapy. When time to an undetectable HCV‐RNA was 1, 2, 4, 8, and 12 weeks, total duration of therapy was 12, 24, 36, 48 and 60 weeks, respectively. Patients who failed to achieve an undetectable HCV‐RNA within 12 weeks discontinued therapy on 12 week. Results: Among the 101 patients treated, 56 (55.4%) achieved sustained virological response (SVR). SVR rate for each treatment duration was 10/10 for 12 weeks, 12/14 for 24 weeks, 18/19 for 36 weeks, 15/26 for 48 weeks, 1/4 for 60 weeks and 0/28 for patients who discontinued therapy at 12 weeks. Mean time to an undetectable HCV‐RNA was 35.5 ± 2.7 days. Mean therapy duration was 27.3 ± 1.4 weeks. Using a cut off value of 21.5 fmol/L of HCV core‐antigen in the first week, SVR could be predicted by sensitivity of 0.91 and specificity of 0.78. Conclusion: IFN‐beta induction therapy resulted in acceptable SVR rates despite short therapy duration. Steep reduction of HCV by IFN‐beta enables us to predict SVR in the first week of therapy.     

Time to viral suppression is not related to achievement of SVR12 in HCV GT1‐infected patients treated with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin

High rates of sustained virologic response at post‐treatment week 12 (SVR12) were achieved in six phase 3 trials of ombitasvir (OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) co‐dosed with ritonavir (PTV/r) + dasabuvir (DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (RBV) in adults with chronic genotype (GT) 1 hepatitis C virus (HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1‐infected patients enrolled in six phase 3 studies of 3D ± RBV. Patients who experienced non‐virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT‐PCR assay (lower limit of quantification, LLOQ =25 IU/mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA <LLOQ. The analysis included a total of 2027 patients. Cumulative proportions of subjects with initial HCV RNA suppression <LLOQ at weeks 1, 2, 4 and 6 were 31%, 81%, 99% and 100%, respectively. SVR12 was achieved by 98%, 97%, 98% and 92% of patients with initial suppression at Weeks 1, 2, 4 and 6, respectively (P=.42, trend test). Across six phase 3 trials of 3D ± RBV, most patients achieved viral suppression by week 2. Time to viral suppression was not associated with subsequent achievement of SVR12, suggesting that on‐treatment virologic monitoring may not be necessary with this regimen.     

Antiviral effect of ribavirin in early non-responders to interferon monotherapy assessed by kinetics of hepatitis C virus RNA and hepatitis C virus core antigen

BACKGROUND/AIMS: To evaluate the efficacy of ribavirin, given in second intention in non-responders to interferon alone, by studying viral kinetics. METHODS: We conducted a trial including 203 patients with chronic hepatitis C, na?ve of treatment. Patients were treated with interferon three times a week with or without ribavirin and amantadine according to response. Viral kinetics were assessed by serial measurements of HCV RNA (bDNA 3.0 and Monitor 2.0) and a new assay, trak-C, able to quantify total Hepatitis C virus (HCV) core antigen. RESULTS: A significant initial drop in HCV RNA or HCV core antigen, under interferon alone, was associated with response to therapy, -4.85+/-1.33 log for HCV RNA in sustained responders versus -1.86+/-1.53 log for others groups, P<0.001. In patients receiving ribavirin in second intention, we also observed a similar drop in HCV RNA and HCV core antigen, predictive of sustained response, -2.67+/-1.26 log for HCV RNA in sustained responders versus -0.44+/-0.49 log in non-responders, P<0.001. CONCLUSIONS: Ribavirin has probably an additional antiviral effect in interferon treated patients. Kinetics of HCV RNA and HCV core antigen under treatment are highly predictive of a sustained virological response.     

Hyperinsulinaemia reduces the 24‐h virological response to PEG‐interferon therapy in patients with chronic hepatitis C and insulin resistance

Summary. Insulin resistance (IR) reduces response to pegylated‐interferon (PEG‐IFN)/ribavirin in chronic hepatitis C (CHC), but the mechanisms are still undefined. We examined the relationship between baseline insulin levels, the main component affecting homeostasis model of assessment – insulin resistance (HOMA‐IR) for assessment of IR in non‐diabetic patients, and the ‘acute’ virological response to PEG‐IFN measured 24 h after the first injection and taken as correlate of intracellular interferon signalling. In 62 patients treated with PEG‐IFN/Ribavirin, serum insulin and HOMA‐IR were assessed at baseline, while hepatitis C virus (HCV)‐RNA was measured at baseline and 24 h, 1, 2, 4 and 12 weeks after treatment initiation. Sustained virological response was examined 24 weeks after therapy discontinuation. Mean baseline insulin was 11.52 ± 8.51 U/L and mean HOMA‐IR was 2.65 ± 2.01 both being significantly higher with advanced liver fibrosis. Hepatitis C virus‐RNA decay observed 24 h after the first injection of PEG‐IFN was significantly lower (0.7 ± 0.8 log) in patients with HOMA ≥3 compared with those with HOMA <3 (1.7 ± 0.8, P = 0.001). A highly significant (r = ?0.42) inverse correlation was observed between baseline insulin levels and the 24‐h HCV‐RNA decay. The difference in early viral kinetics between patients with HOMA ≥3 or <3 resulted in a significant difference in the percentage of patients achieving rapid (week 4) and sustained virological response. Multivariate analysis, inclusive of patient age, HCV genotype and fibrosis stage, identified baseline insulin levels as the main independent variable affecting the 24‐h response to PEG‐IFN. Hyperinsulinaemia reduces the cellular response to Pegylated‐interferon in CHC with IR. Strategies to reduce insulin levels before initiation of treatment should be pursued to improve efficacy of anti‐viral treatment.     

Comparison of HCV core antigen activity by ELISA and amount of HCV RNA by branched DNA assay

Recently an assay system for direct detection of HCV RNA using a branched DNA probe (branched DNA assay: bDNA assay) has been developed for practical use. Concurrently, a method for direct quantitation of HCV particles by measurement of serum HCV core antigen activity has also been established. We compared the results of serum HCV RNA quantitation by bDNA assay and HCV core antigen measurements, and found a highly significant correlation between the two methods (R² = 0.816).     

Mutations in the NS5A and E2‐PePHD regions of hepatitis C virus genotype 1b and response to combination therapy of interferon plus ribavirin

Background/aims: Combination therapy with interferon (IFN) and ribavirin is the current standard treatment for chronic hepatitis C, but the efficacy is still not satisfactory, especially for genotype 1b. NS5A and E2 proteins of hepatitis C virus (HCV) may repress the IFN‐induced RNA‐dependent protein kinase (PKR), and thus have the potential to influence the response of HCV to IFN therapy; however, this issue remains controversial. Methods: Nucleotide sequences of the PKR‐eIF2α phosphorylation homology domain (E2‐PePHD) and PKR‐binding domain (NS5A‐PKR bd) of the HCV genome were analyzed by amplification and direct sequencing in 30 HCV genotype 1b patients who had been treated with IFN and ribavirin. Results: Nine (30%) patients achieved a sustained virological response (SVR) to combination therapy. Pretreatment variables and amino acid substitutions were compared between responders and non‐responders. The responders were younger than non‐responders (37.2±10.4 vs. 45.4±9.5 years, P=0.017), whereas no significant statistical differences were found in the number of amino acid substitutions in NS5A and E2‐PePHD regions between the two groups. Conclusions: Genetic heterogeneity in NS5A and E2‐PePHD regions of the HCV genome may not serve as a predictor for treatment outcome with combination therapy in Taiwanese patients with chronic HCV genotype 1b infection.     

Early identification of achieving a sustained virological response in chronic hepatitis C patients without a rapid virological response

Background and Aim: A number of hepatitis C virus (HCV) patients without a rapid virological response (RVR) achieved a sustained virological response (SVR) with peginterferon‐α‐2a/ribavirin. The aim of this study was to identify factors associated with SVR in non‐RVR patients. Methods: Baseline and on‐treatment factors were used to explore the prognostic factors for SVR in 113 HCV genotype‐1 (HCV‐1) and 20 HCV‐2 non‐RVR patients in two randomized trials. Results: The SVR rate in HCV‐1 patients with a complete early virological response (cEVR) and partial early virological response was 91.9% versus 45% (P < 0.001) and 21.4% versus 10% (P = 0.62), respectively, after 48 and 24 weeks of treatment. The SVR rate in HCV‐2 patients with a cEVR was 90.9% versus 57.1% (P = 0.25), respectively, after 24 and 16 weeks of treatment. Multivariate analysis showed that cEVR and standard regimen were independently associated with SVR. Viral kinetic study revealed that HCV viral loads < 10 000 IU/mL at week 4 were the best predictor of cEVR for both HCV‐1 and HCV‐2 non‐RVR patients with the accuracy of 81% and 95%, respectively, and also of SVR with the accuracy of 78% and 92%, respectively, in patients receiving standard of care. The most important independent predictors for cEVR were HCV viral loads < 10⁴ IU/mL at week 4, followed by increased ribavirin dose within 12 weeks of treatment. Conclusions: Achieving a cEVR with standard of care is the most important predictor of SVR in non‐RVR patients. Week 4 viral loads < 10 000 IU/mL could accurately predict cEVR early and following SVR in non‐SVR patients.     

Non‐response to daclatasvir and asunaprevir therapy in patients co‐infected with hepatitis C virus genotypes 1 and 2

Direct‐acting antiviral agents for hepatitis C virus (HCV) have been developed such as combined daclatasvir (DCV) and asunaprevir (ASV) treatment. This typically enables HCV serotype 1 patients to achieve a high sustained virological response rate, but a small number of such patients fail to respond to therapy. We investigated three HCV patients who showed no response to DCV and ASV therapy. Hepatitis C genotyping was undertaken in the three patients using nested polymerase chain reaction and polymerase chain reaction direct sequencing in the core region of the HCV genome. All three patients possessed HCV serotype 1, and no mutations were identified in either the non‐structural protein 3 or 5A region. The three patients were shown to be co‐infected with HCV genotypes 1 and 2 because genotypes 2a and 2b were also identified. This is the first report into failed response to DCV and ASV therapy in patients co‐infected with HCV genotypes 1 and 2.     

两种实时荧光定量聚合酶链反应检测血清HCV RNA的比较

目的 比较全自动病毒载量检测系统(COBAS TaqMan)和国产荧光定量PCR试剂盒对血清HCV RNA载量的检测结果,探讨两种检测方法在临床诊断和治疗中的应用价值.方法 收集26例慢性丙型肝炎患者抗病毒治疗前和治疗过程中2、4、8、12、24、36和48周的系列血标本,共168份,采用COBAS TaqMan 48全自动分析系统和广州某国产TaqMan实时PCR试剂盒分别检测系列血清中的HCV RNA载量.统计学处理采用x2检验和t检验.结果 当血清HCV RNA≥1×104IU/mL时(0周),COBAS检测和国产试剂盒均能很好测定HCV载量,而且国产试剂盒检测值为1.35×107IU/mL高于COBAS检测值2.21×106IU/mL,差异有统计学意义(t=2.05,P<0.05);血清HCV RNA<1×104IU/mL时(2～48周),COBAS检测出的HCV阳性率为21.4%(30/140),远高于国产试剂盒的1.4%(2/140),差异有统计学意义(t=3.66,P<0.01);治疗4周时,COBAS检测26例患者中14例血清HCV为阳性,12例病毒载量低于检测下限,获得快速病毒学应答(RVR);国产试剂盒检测结果为3例血清HCV为阳性,23例获得RVR.COBAS与国产试剂盒梧比,转阴率差异有统计学意义(x2=10.575,P<0.01).治疗12周时,COBAS检测完全早期病毒学应答(cEVR)率为95.7%(22/23),国产试剂盒检测的cEVR为100%(17/17),差异无统计学意义(x2=0.726,P>0.05).结论 国产荧光定量PCR试剂盒可用于HCV疑似患者的筛查和高HCVRNA载量者的确诊,对于低HCV RNA载量的疑似患者和抗病毒治疗过程中HCV载量的检测,COBAS则更为敏感.

Abstract：

Objective To compare the plasma hepatitis C virus(HCV)RNA levels detected by the fully automated viral load detection system(COBAS TaqMan)and the national real-time quantitative polymerase chain reaction(PCR)kit,and to investigate the clinical application value of these two methods in clinical practice.Methods A total of 168 serial plasma samples collected from 26 patients with chronic hepatitis C(CHC)before and at week 2,4,12,24,36 and 48 of antiviral treatment were detected by both COBAS Taqman 48 analyzing system and the national real-time quantitative PCR kit.The results of two methods were compared by chi square test and t test.Resnlts Both COBAS and national kit showed great positive detecting results when HCV RNA≥1×104IU/mL(at week O),and the virus load value detected by national kit was significantly higher than that detected by COBAS(t=2.05,P<0.05).However,when HCV RNA<1×104(at week 2-48),the positive rate of HCV detected by COBAS was significantly higher than that detected by national kit (t=3.66,P<0.01).At week 4 of treatment,the rapid virological response(RVR)rate was 46.2 % (12/26)detected by COBAS,while that was 88.5%(23/26)detected by national kit,and the difference was significant(x2=10.575,P<0.01).At week 12 of treatment,the complete early virological response(cEVR)was 95.7%(22/23)detected by COBAS,while that was 100%(17/17)detected by national kit,and the difference was not significant(x2=0.726,P>0.05).Conclusions The national TaqMan real-time quantitative PCR kits could be used to screen the suspected cases of HCV infecrion and to diagnose CHC cases with high HCV virus load.COBAS detection is more sensitive in cases with low HCV virus load and in on-treatment monitor during anti-HCV therapy.     

Comprehensive longitudinal analysis of hepatitis C virus (HCV)‐specific T cell responses during acute HCV infection in the presence of existing HIV‐1 infection

Summary. The aim of this study was to study the development of HCV‐specific T cell immunity during acute HCV infection in the presence of an existing HIV‐1 infection in four HIV‐1 infected men having sex with men. A comprehensive analysis of HCV‐specific T cell responses was performed at two time points during acute HCV infection using a T cell expansion assay with overlapping peptide pools spanning the entire HCV genome Three patients with (near) normal CD4+ T cell counts (range 400–970 × 10⁶/L) either resolved (n = 1) or temporary suppressed HCV RNA. In contrast, one patient with low CD4+ T cell counts (330 × 10⁶/L), had sustained high HCV RNA levels. All four patients had low HCV‐specific CD8+ T cell responses, and similar magnitudes of CD4+ T cell responses. Interestingly, individuals with resolved infection or temporary suppression of HCV‐RNA had HCV‐specific CD4+ T cell responses predominantly against nonstructural (NS) proteins. While the individual with high HCV RNA plasma concentrations had CD4+ T cell responses predominantly directed against Core. Our data show that an acute HCV infection in an HIV‐1 infected person can be suppressed in the presence of HCV‐specific CD4+ T cell response targeting non‐structural proteins. However further research is needed in a larger group of patients to evaluate the role of HIV‐1 on HCV‐specific T cell responses in relation to outcome of acute HCV infection.     

Very early prediction of response to HCV treatment with PEG‐IFN‐alfa‐2a and ribavirin in HIV/HCV‐coinfected patients

Summary. The objective of this study was to find very early viral kinetic markers to predict nonresponse to hepatitis C virus (HCV) therapy in a group of human immunodeficiency virus (HIV)/HCV‐coinfected patients. Twenty‐six patients (15 HCV genotype‐1 and 11 genotype‐3) were treated with a 48‐week regimen of peginterferon‐alfa‐2a (PEG‐IFN) (180 μg/week) and weight‐based ribavirin (11 mg/kg/day). Samples were collected at baseline; 4, 8, 12, 18, 24, 30, 36 and 42 h; days 2, 3, 4, 7, 8, 15, 22, 29, 43 and 57 then weekly and monthly. Five patients discontinued treatment. Seven patients (27%) achieved a sustained virological response (SVR). Nadir HCV RNA levels were observed 1.6 ± 0.3 days after initiation of therapy, followed by a 0.3‐ to 12.9‐fold viral rebound until the administration of the second dose of PEG‐IFN, which were not associated with SVR or HCV genotype. A viral decline <1.19 log for genotype‐1 and <0.97 log for genotype‐3, 2 days after starting therapy, had a negative predictive value (NPV) of 100% for SVR. The day 2 virological response had a similar positive predictive value for SVR as a rapid virological response at week 4. In addition, a second‐phase viral decline slope (i.e., measured from day 2 to 29) <0.3 log/week had a NPV = 100% for SVR. We conclude that first‐phase viral decline at day 2 and second‐phase viral decline slope (<0.3 log/week) are excellent predictors of nonresponse. Further studies are needed to validate these viral kinetic parameters as early on‐treatment prognosticators of nonresponse in patients with HCV and HIV.     

Association of a genetic polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 with hepatitis C virus infection and hepatitis C virus core antigen levels in subjects in a hyperendemic area of Japan

Background  The clinical course of chronic hepatitis C virus (HCV) infection is strongly associated with insulin resistance and obesity. The K121Q polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP)-1 gene and the rs7566605 genotype located near insulin-induced gene 2 have been shown to be associated with insulin resistance and obesity. This study examined whether the K121Q polymorphism in ENPP1 or the rs7566605 genotype is associated with the clinical course of HCV infection. Methods  The relationships between the clinical characteristics of 469 anti-HCV antibody-seropositive subjects (353 were positive for HCV core antigen or RNA, whereas 116 were negative for HCV RNA) and the polymorphisms were analyzed. Results  No significant differences in body mass index, plasma glucose level, serum insulin level, and other biochemical markers were observed between subgroups of subjects with different genotypes at the K121Q polymorphism or rs7566605. The frequency of the homozygous wild-type genotype at K121Q in HCV carriers, however, was significantly higher than that in subjects who were negative for HCV RNA (84.5% vs. 75.9%; P < 0.05). Moreover, in HCV carriers, HCV core antigen levels in subjects homozygous for the wild-type genotype at K121Q were significantly higher than in heterozygous carriers of K121Q (5358 fmol/l vs. 4002 fmol/l; P = 0.04). In contrast, the rs7566605 genotype was not associated with hepatitis C viremia or with the HCV core antigen level. Conclusions  The K121Q variant of ENPP1 may be associated with hepatitis C viremia and core antigen levels in HCV carriers.     

NS5A mutations predict biochemical but not virological response to interferon-α treatment of sporadic hepatitis C virus infection in European patients

The NS5A region of the hepatitis C virus (HCV) genome has been reported by Japanese but not European investigators to be a significant factor in predicting interferon (IFN) response patients with HCV of genotype 1. We correlated the NS5A region with treatment outcome in patients with sporadic HCV infection. Twenty‐eight patients (10 men, 18 women, mean age 60 ± 2 years) with histologically proven HCV chronic hepatitis, genotype 1b, were treated with 6 MU IFN‐α for 6 months. The 6954–7073 area of the NS5A region was directly sequenced for nucleotide and amino acids mutations and the results were related to biochemical and virological response. None of the patients had a strain with nucleotide sequence identical to the Japanese HCV‐J. However, in five strains the nucleotide mutations led to synonymous amino acids and the amino acid sequences were identical to the prototype Japanese strain. Only 2/28 patients had four or more amino acid mutations (mutant strains) while 21 demonstrated an intermediate type and five belonged to the wild‐type. The most frequent non‐synonymous substitution was at position 6982 (A→G) corresponding to an amino acid change at codon 2218 (His→Arg). All patients with the wild‐type were biochemical nonresponders while the two patients with the mutant strains had a sustained biochemical response. Twenty‐three percent of the intermediate type had a sustained biochemical response. NS5A mutations predict the biochemical but not the virological response of patients. Virological response was poor and unrelated to the type of HCV strain. Biochemical responders had significantly lower amino acid mutations (1.14 ± 0.19) compared with nonresponders (2.57 ± 1.4, P < 0.003) as well as lower aminotransferase values (P < 0.01). Hence, mutational analysis of the NS5A region showed that our patients have a mutational profile similar to the European studies with a wild‐type that is slightly different from the Japanese HCV‐J sequence. The biochemical, but not the virological response to IFN‐α is similar to the Japanese studies, with no response of the patients with wild‐type sequence, a good response in the limited number of patients with mutant strains and 23% response rate in the patients with intermediate type sequences.     

Pegylated interferon plus ribavirin therapy improves pancreatic β‐cell function in chronic hepatitis C patients

Background/Aims: Pretreatment insulin resistance (IR) is associated with treatment response to peginterferon plus ribavirin (PegIFN/RBV) combination therapy in chronic hepatitis C (CHC) infection. However, the impact of PegIFN/RBV therapy on both IR and β‐cell function in CHC patients has rarely been investigated. Methods: A total of 277 non‐diabetic patients treated with PegIFN‐α and weight‐based RBV, with 80/80/80 adherence, were recruited. Their IR and β‐cell function by homeostasis model assessment model (HOMA‐IR and HOMA‐%B) before treatment and at 24 week after treatment [end of follow‐up (EOF)] was measured. Results: A sustained virological response (SVR) was achieved by 79.4% (220/277) of all patients: 63.6% (75/118) of genotype‐1 and 91.2% (145/159) of genotype‐non‐1 patients. There was no significant change of HOMA‐IR post‐therapy (2.25 ± 2.46 vs 2.04 ± 2.12, P=0.42). By contrast, there was a significant reduction of HOMA‐%B of all patients at EOF (122.9 ± 145.2 vs 92.4 ± 73.2, P=0.001), particularly in those responders (119.1 ± 142.1 vs 89.6 ± 70.3, P=0.002). In 80 patients with high baseline HOMA‐IR, both HOMA‐IR and HOMA‐%B decreased significantly at EOF, irrespective of SVR achievement. Conclusion: This study demonstrated pancreatic β‐cell function was ameliorated by PegIFN/RBV therapy in CHC patients, particularly in those responders.     

Clinical usefulness of total hepatitis C virus core antigen quantification to monitor the response to treatment with peginterferon alpha-2a plus ribavirin*

Summary. Early virological response may predict outcome following treatment with peginterferon alpha-2a and ribavirin in patients chronically infected with hepatitis C virus (HCV). As total HCV core antigen may constitute an alternative direct marker to HCV RNA for assessing the levels of viraemia in such patients, we evaluated the correlation between HCV core antigen and HCV RNA, and whether HCV core antigen at baseline, 4 and 12 weeks after treatment could predict sustained virological response (SVR) to combined therapy, in comparison with HCV RNA. A total of 290 serum samples from 58 previously treatment naïve chronic HCV patients were examined for HCV core antigen and HCV-RNA by means of quantitative HCV RNA when receiving combination therapy for the first time. SVR was significantly associated with basal HCV core antigen but not with HCV RNA. There was a good correlation between HCV core antigen and HCV RNA (r² = 0.781). The negative predictive value of HCV core antigen testing in predicting nonresponse at weeks 4 and 12 were 75 and 100%, and for undetectable or a 2-log drop in HCV RNA were 69.6 and 75% respectively. HCV core antigen detection is quick, and easy to perform alternative to HCV RNA, and could be used as a marker of HCV viraemia for monitoring the progress of therapy.