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Replicated Association Between an IL28B Gene Variant and a Sustained Response to Pegylated Interferon and Ribavirin - full text pdf attached
Gastroenterology June 2010
Jeanette J. McCarthy, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina
Josephine H. Li, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina
Alexander Thompson, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
Sunil Suchindran, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina
Xiang Qian Lao, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina
Keyur Patel, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
Hans L. Tillmann, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
Andrew J. Muir, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
John G. McHutchison, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina
Received 20 October 2009; accepted 10 February 2010. published online 22 February 2010.
ABSTRACT
Background & Aims
Patients with chronic hepatitis C virus (HCV) infections are treated with pegylated interferon and ribavirin (PEG-IFN/RBV), which is effective in less than 50% of those infected with HCV genotype 1. Genome-wide association studies have linked response to PEG-IFN/RBV with common single nucleotide polymorphisms in the vicinity of interferon (IFN)-λ genes on chromosome 19. We investigated the association between the polymorphism rs12979860 and treatment response in a diverse cohort of chronic HCV patients.
Methods
A cross-sectional study of 1021 consecutive patients enrolled in the Duke Hepatology Clinic Research Database and Biorepository. We analyzed DNA, clinical and demographic data, along with validated data of the response of 231 subjects to PEG-IFN/RBV. The study included Caucasians (n = 178), African Americans (n = 53), and HCV genotypes 1 (n = 186) and 2/3 (n = 45). The rs12979860 genotype was tested for an association with sustained virologic response, defined as undetectable levels of HCV RNA 24 weeks after treatment ended.
Results
The rs12979860 CC genotype (found in ∼40% of Caucasians) predicted a sustained virologic response to therapy among Caucasians (odds ratio, 5.79; 95% confidence interval, 2.67–12.57; P = 9.0 × 10−6), independent of HCV genotype and other covariates. Rs12979860 CC predicted a sustained response with 78% specificity and 65% sensitivity in patients infected with HCV genotype 1).
Conclusions
rs12979860 genotype is a significant independent predictor of response to PEG-IFN/RBV in patients with chronic HCV infection; tests for this genotype might be used to determine the best course of treatment for patients considering antiviral therapy.
Infection with the hepatitis C virus (HCV) is a global health problem, with worldwide estimates of 120–130 million carriers.1 In the United States alone, 3–4 million people are thought to be infected, representing 1.6% of the population.2, 3 Chronic HCV infection can lead to progressive liver disease, resulting in cirrhosis and complications including decompensated liver disease and hepatocellular carcinoma leading to the need for transplantation.2, 3 The current standard-of-care treatment for suitable patients with chronic HCV infection consists of pegylated interferon alfa 2a or 2b (PEG-IFN) given by injection in combination with oral ribavirin (RBV), for 24 or 48 weeks, dependent on HCV genotype. This treatment is not only costly, but is associated with significant side effects resulting in reduced compliance and fewer patients completing treatment. Only about half of treated subjects achieve a sustained virologic response (SVR).4, 5, 6 For all these reasons, decisions regarding treatment with current standard-of-care IFN-based therapy are complex and based on the balanced assessment of host and viral determinants that aid in predicting virologic response. HCV genotype, in particular, is used in making treatment decisions: patients with HCV genotype 2/3 have a relatively high rate of SVR (70%–80%) with 24 weeks of treatment, whereas those infected with HCV genotype 1 (representing about 70%–75% of infected persons in the United States) have a much lower rate of SVR (40%) despite 48 weeks of treatment.6
Recently, several highly correlated common single nucleotide polymorphisms (SNPs) on a linkage disequilibrium block in the vicinity of 3 IFN-λ genes on chromosome 19, encoding interferon λ1 (IL29), λ2 (IL28A), and λ3 (IL28B), have been implicated in response to PEG-IFN/RBV among patients infected with HCV genotype 1 from 3 genome-wide association studies.7, 8, 9 The risk genotype associated with nonresponse to therapy was more common in African Americans and thought to account for half of the observed ethnic variation in treatment response. Paradoxically, the responder genotype was associated with higher viral load.
We sought to confirm and extend our understanding of this recently reported genetic association in a cohort of patients with chronic HCV infection from a large tertiary care setting, including subjects infected with HCV genotypes 2 and 3.
Results
Association of rs12979860 Genotype With SVR to PEG-IFN/RBV by Race
A description of the cohort used in our analysis of response to PEG-IFN/RBV is shown in Table 1. Patients predominantly were Caucasian, infected with HCV genotype 1, and broadly representative of a tertiary care chronic HCV cohort. Among patients treated with PEG-IFN/RBV, those included in this analysis differed only slightly from those excluded, with more HCV genotype 2/3–infected subjects (20% vs 11%; P = .02). As expected, responders to standard-of-care PEG-IFN/RBV treatment were characterized as having significantly lower viral load, being younger, of Caucasian race, infected with HCV genotype 2 or 3, and being treatment-naive. Rs12979860 allele frequencies differed by race and were consistent with those previously reported (Caucasian C, 0.63; T, 0.37; African American C, .40; T, .60). In the overall cohort, a nominal deviation in Hardy–Weinberg equilibrium was found for Caucasians (P = .02), which could not be attributed to genotyping error, but possibly reflects an underlying association between genotype and chronic HCV infection.
Figure 2 illustrates how, among Caucasians, rs12979860 genotype was associated significantly with response to PEG-IFN/RBV, with the greatest effect seen when comparing subjects with two copies of the C allele (CC genotype) with those with one or no copies. Therefore, all subsequent analyses considered the CC genotype vs CT/TT. This association remained significant in multivariable analysis controlling for age, sex, HCV genotype, treatment history, and fibrosis, where presence of the CC genotype conferred a nearly 6-fold increased odds of SVR relative to the CT/TT genotype (odds ratio, 5.79; 95% confidence interval, 2.67–12.57; P = 9.0 × 10−6). Among Caucasians, there was no difference in the effect of rs12979860 on SVR comparing subjects with HCV genotype 1 and 2/3, or between those with a prior treatment history and those treatment naive at baseline (rs12979860 genotype by trait interactions, P > .05).
Figure 2. Association between rs12979860 genotype and PEG-IFN/RBV treatment response in Caucasian and African American chronic HCV patients from our cohort. (A) Caucasians, (B) African Americans. Numbers with SVR out of all with that genotype are shown below each rs12979860 genotype. Chi-squared P values for Caucasians are adjusted for age, sex, HCV genotype, treatment history, and fibrosis. P values in African Americans are from the Fisher exact test and are not adjusted because of the small sample sizes.
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African Americans comprised only 23% of our cohort and predominantly were infected with genotype 1 HCV (98%), and 57% were treatment-naive. As illustrated in Figure 2, no association was found between rs12979860 genotype and treatment response in African Americans in our study, and the difference in the rs12979860 treatment response association between African Americans and Caucasians did not reach significance (rs12979860 by race interaction, P = .34). However, it should be noted that the estimated proportion of SVR among patients with the CC genotype, 0.125 (1 of 8), is unstable because of the small sample size, resulting in a wide confidence interval (0.003–0.53), and thus making it difficult to draw inference.
To assess the relative contribution of important covariates to treatment response, we examined the effect of each covariate in a multivariable model. Table 2 shows the relative effect of all covariates on treatment response in univariable and multivariable models. HCV genotype was the strongest predictor of treatment response in univariable and multivariable analyses that did not include the rs12979860 genotype. Inclusion of rs12979860 in the model attenuated the effects of HCV genotype and enhanced the association with viral load. Rs12979860 genotype emerged as the strongest factor associated with treatment response; other independently associated factors included HCV genotype, viral load, age, and treatment history. Inclusion of rs12979860 genotype in the model improved the C statistic (from 0.75 to 0.82) as well as the Nagelkerke R2 (from 0.25 to 0.38). In the current study, inclusion of the IL28B genotype in the model resulted in reclassification of responders (30%) and nonresponders (56%), for an overall Net Reclassification Improvement (0.86) that was highly significant (P = 2.3 × 10−7).
To assess the relative value of rs12979860 compared with HCV genotype, we calculated sensitivity, specificity, and likelihood ratios in our cohort of Caucasian subjects (Table 3). Comparing rs12979860 CC genotype with HCV genotype 2/3 revealed HCV genotype as having somewhat better specificity, but rs12979860 genotype has better sensitivity and is more common, found in 38% of chronic HCV patients (compared with ∼25% prevalence of HCV genotypes 2/3). Performance of rs12979860 among the subset of HCV genotype 1 subjects, or among the subset of treatment-naive subjects, mirrors that in all subjects with HCV genotypes 1, 2, and 3 combined.
Effect of rs12979860 on Treatment Relapse Among Caucasians
Among 111 (62%) Caucasian subjects who failed to achieve SVR to PEG-IFN/RBV, 29 (26%) were classified as relapsers. The frequency of the rs12979860 CC genotype in this group was between that observed for the SVR and end-of-treatment nonresponder groups. However, only the difference found between relapsers and end-of-treatment nonresponders was significant, suggesting that rs12979860 CC genotype influences end-of-treatment response and does not distinguish accurately between patients with a relapse response and those with a SVR (Figure 3).
Association With HCV Genotype
HCV genotype data were available for a larger group of patients than were used for analysis of treatment response (n = 649 Caucasians). We compared the rs12979860 genotype frequencies between Caucasians infected with HCV genotypes 1, 2, and 3 (Figure 4). Rs12979860 CC was most common in genotype 3 patients (55%), followed by genotype 2 (46%) and genotype 1 (33.5%; P = .0007). To correct for possible referral bias, we examined this association in the subset of naive patients undergoing treatment with PEG-IFN/RBV and observed the same trend (data not shown).
Association With Viral Load
Off-treatment viral load measures were available for 301 Caucasians with chronic HCV infection from our cohort, 277 of whom had complete data on covariates as well and could be used in our analysis to determine the association between rs12979860 genotype and viral load. The odds of having a higher quantitative viral load in patients with rs12979860 CC genotype were twice that of patients with genotype CT/TT in analysis controlling for age, sex, HCV genotype, and fibrosis (odds ratio, 2.13; 95% confidence interval, 1.24–3.66; P = .0061).
Discussion
Treatment decisions in patients with chronic hepatitis C infection currently are based on clinical, demographic, and virologic characteristics of infected patients. Although these may be helpful from a population point of view, for any individual patient and provider, these baseline pretreatment characteristics are inaccurate in predicting treatment response in hepatitis C patients infected with genotype 1, the most common genotype found in the United States. We have confirmed in this study that the recently identified common genetic variant in the IFN-λ gene region is associated strongly with response to standard-of-care PEG-IFN/RBV in a tertiary care setting. The association among Caucasians thus was validated outside of the clinical trial setting. Because of the limited sample size of African Americans and other racial groups in this current study, we had inadequate power to detect statistical association in these groups, as was observed by Ge et al.7 Nonetheless, inclusion of rs12979860 genotype and race in a multivariable model caused an attenuation of the effect of race on treatment response, indicating that the effect of race may be mediated in part through this polymorphism.
Our results extend the observations of Ge et al7 and indicate that, among Caucasians, rs12979860 has a high specificity, similar to HCV genotype, the current best baseline indicator used for identifying patients who will achieve a SVR to antiviral therapy. Used in conjunction with HCV genotype, rs12979860 may provide additional discriminatory power to identify likely responders to treatment.
Another interesting observation was the significantly different frequency of the rs12979860 genotype according to HCV genotype in Caucasian patients. HCV genotype 1–infected patients were less likely to have the rs12979860 response genotype than were patients infected with HCV genotypes 2 or 3. Although interesting, this relationship does not fully explain why patients infected with HCV genotypes 2 or 3 have significantly higher sustained response rates compared with those infected with HCV genotype 1; both the gene variant and HCV genotype remain independently associated with treatment response in the multivariable models we ran. Nonetheless, this observation theoretically could have some biological bearing on the development of persistent or chronic (vs spontaneously cleared) HCV infection. The data could be interpreted in the context of a case-only study design, where an association between 2 factors (rs12979860 and HCV genotype) among cases of chronic HCV may reflect interaction between rs12979860 and HCV genotype in the development of chronic HCV.18, 19 Based on these results, we would hypothesize that subjects with both HCV genotype 2/3 and rs12979860 CC would be more likely to develop chronic HCV and hence less likely to clear the virus spontaneously than those with HCV genotype 1 and rs12979860 CT/TT. Although this relationship may seem counterintuitive on account of HCV genotype 2/3 subjects having a significantly higher rate of treatment-induced viral clearance, it warrants further exploration in appropriate prospective studies of spontaneous clearance. We also considered that the association could have been due to referral bias, whereby chronic HCV patients who are difficult to treat may be overrepresented among the Duke cohort, and these patients would be more likely to be HCV genotype 1 and rs12979860 CT/TT genotype. This bias could lead to an overestimate of the association between rs12979860 genotype and HCV genotype. However, when we analyzed a subset of treatment-eligible patients with no prior treatment history we found a similar trend of association.
Although the rs12979860 SNP showed a remarkably strong association with treatment response in both the study by Ge et al7 and our replication study, the exact causal variant underlying the observed genetic association has not been identified. This SNP lies closest to 2 genes encoding for IFN-λ proteins, λ2 and λ3. IFN-λ have been studied previously in the context of HCV infection and shown to suppress HCV replication in vitro.20, 21, 22 It is possible that the causal variant affects expression or function of one of these antiviral genes, which may in turn affect viral control.
Interestingly, Ge et al7 reported a paradoxic relationship to viral load in that the responder allele of rs12979860 was associated statistically with a higher baseline viral load, inconsistent with the clinical observation that higher baseline viral load typically is associated with a poorer treatment response.4, 5, 6 We also confirmed this paradoxic association with off-treatment viral load in our expanded cohort of Caucasian patients from a tertiary care setting. The exact mechanism underlying this genetic association with high viral load and yet increased likelihood of treatment response remains to be determined.
There are several important clinical implications of this genetic association originally reported by Ge et al7 in a clinical trial population and confirmed in the present study in a tertiary care population. First, the rs12979860 SNP may be useful in determining which chronic HCV genotype 1 patients would be most likely to respond to treatment with PEG-IFN/RBV. Given the high prevalence of the rs12979860 responder genotype in Caucasians (∼40%), this could have a substantial impact on treatment decision making. Our data support the potential utility of rs12979860 in predicting SVR in Caucasians, regardless of treatment history. However, additional prospective studies are needed to determine the true predictive value of this marker among all treatment-eligible patients, including those from other racial/ethnic and HCV genotype groups, and taking into account noncompliant and relapsing patients as well. Ultimately, chronic HCV patients with the rs12979860 responder genotype may be more motivated to comply with treatment, or to undergo treatment in the presence of mild underlying liver disease, knowing that they have a higher likelihood of SVR.
These important genetic findings related to treatment response in patients with chronic hepatitis C infection suggest the possibility of personalized medicine for the treatment of this disease. Clinical trials are now necessary to determine whether HCV genotype 1–infected patients with the favorable rs12979860 responder genotype would benefit equally from shorter treatment duration with our current therapies or future therapies, thus reducing the cost and side effects associated with longer-term treatment. How the rs12979860 responder genotype influences the outcomes to future antiviral strategies, including those based on protease and polymerase inhibition, requires immediate attention and investigation. Understanding the clinical implications of this genetic, biologically plausible finding will be a major research agenda and priority.
Friday, July 2, 2010
IL28B polymorphism determines treatment response of patients with hepatitis C
IL28B polymorphism determines treatment response of patients with hepatitis C genotypes 2 or 3 who do not achieve a rapid virologic response
Alessandra Mangia, Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Alexander J. Thompson, Duke Clinical Research Institute and Duke University Medical Center, Durham, NC, USA
Rosanna Santoro, Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Valeria Piazzolla, Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Hans L. Tillmann, Duke Clinical Research Institute and Duke University Medical Center, Durham, NC, USA
Keyur Patel, Duke Clinical Research Institute and Duke University Medical Center, Durham, NC, USA
Kevin V. Shianna, Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, NC, USA
Leonardo Mottola, Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Daniela Petruzzellis, Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Donato Bacca, Department of Internal Medicine, Hospital Castrano, Italy
Vito Carretta, Department of Internal Medicine Hospital Venosa, Italy
Nicola Minerva, Department of Internal Medicine, Hospital Canosa, Italy
David B. Goldstein, Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, NC, USA
John G. McHutchison, Duke Clinical Research Institute and Duke University Medical Center, Durham, NC, USA
Received 17 February 2010; received in revised form 23 April 2010; accepted 25 May 2010. published online 04 June 2010.
Accepted Manuscript
Abstract
Background & Aims
Polymorphisms in the region of the interleukin (IL)28B gene on chromosome 19 have been associated with peginterferon-a (pegIFN)-induced clearance of genotype 1 hepatitis C virus (HCV); there are no data for patients with genotypes 2 or 3 (G2/3) HCV. We evaluated the effects of IL28B polymorphisms on response to treatment with pegIFN and ribavirin in a well-characterized cohort of G2/3 patients.
Methods
DNA was analyzed from 268 patients (Caucasian, G2=213, G3=55). Patients were randomly assigned to groups that received standard (24 weeks, SD24, n=68) or variable durations of therapy. Patients that received variable durations and had a rapid virological response (RVR) were treated for 12 weeks (VD12, n = 122); those without a RVR were treated for 24 weeks (VD24, n=78). IL28B genotypes (rs12979860) were analyzed for association with treatment response.
Results
The frequencies of the IL28B genotypes were: CC=37%, CT=48%, TT=15% ; 82% of patients with the CC genotype achieved a SVR, compared to 75% with the CT and 58% with the TT genotypes (P = 0.0046). Differences between IL28B genotypes were greatest among patients who failed to attain RVR (VD24 SVR rates: CC=87%, CT=67%, and TT=29%, P=0.0002). Among patients with RVRs (61%), the IL28B genotype was not associated with SVR (>70% for all IL28B genotypes). In a multi-variable logistic regression model, IL28B genotype predicted SVR (odds ratio=1.76; 95% confidence interval=1.16 - 2.7).
Conclusions
An IL28B polymorphism was associated with a SVR in patients infected with genotypes 2 or 3 HCV who did not achieve a RVR. Analysis of IL28B genotype might be used to guide treatment for these patients.
INTRODUCTION
Several viral and host-related factors determine the outcome of peginterferon-␣ (PegIFN) and ribavirin (RBV) treatment in patients with chronic hepatitis C virus (HCV) infection. In addition to viral genotype, serum HCV RNA level and stage of hepatic fibrosis, host genetic factors have recently been identified to influence treatment responsiveness in patients with chronic hepatitis C. Single nucleotide polymorphisms (SNPs) on a linkage disequilibrium block encompassing two interferon lambda genes on chromosome 19 have been strongly associated with response to pegIFN plus RBV combination treatment in three genome wide association studies of HCV genotype 1 infected patients 1-3. The strongest association signal to date has been for the SNP rs12979860 1. Adherent patients with the CC genotype of rs12979860 were more than twice as likely to respond to 48 weeks of treatment as compared to the non-CC genotypes1. Although the mechanism by which this genetic variant acts remains unclear, it is likely to influence innate antiviral immune responses. The influence of this genetic variation on response to shorter treatment courses in patients chronically infected with genotype 2 or 3 HCV is not known.
The current standard therapy for HCV genotype 2 and 3 infection is 24 weeks of pegIFN plus RBV, which cures approximately 80% of patients 4. In recent years, refinements to this regimen have been developed to minimize side effects and costs. In patients with low viral load at baseline who attain week 4 rapid virological response (RVR), 12 – 16 weeks of therapy is associated with rates of SVR that are comparable to those attained after a standard 24 weeks of treatment 5-7 . Although relapse rates may be somewhat higher with shorter therapy 8, the cost-effectiveness of this approach has been demonstrated 6, 9. Individualized therapy for patients with genotype 2/3 HCV infection according to RVR has recently been included in a number of European treatment guidelines 10, 11.
We have now investigated the relevance of IL28B genetic variation to treatment response in a well characterized cohort of European patients with genotype 2 or 3 HCV infection who were treated with pegIFN-alpha-2b and weight-based RBV for 12 or 24 weeks duration according to week 4 virological response, as previously published 5.
DISCUSSION
To our knowledge this is the first report of the role and relevance of the recently described IL28B genetic polymorphism to PegIFN and RBV treatment outcome in the setting of chronic infection with genotype 2 or 3 HCV. This unique cohort, from a prospectively performed landmark clinical trial 5, has allowed us to carefully evaluate the interaction between this genetic determinant and treatment response in patients who received a variable duration of therapy based upon week 4 virologic response.
The data indicate that the IL28B polymorphism is relevant to treatment outcome, although the effect size was attenuated in these genotype 2/ 3 infected European patients, compared to the original observation in North American patients with genotype 1 HCV infection (genotype 2/3: 1.76 [95% CI 1.16 – 2.66], Table 4A, vs genotype 1: OR 5.2 [95%CI 4.1 – 6.7] 14). The attenuation of overall effect size was largely due to the much higher rates of RVR that occurred in the genotype 2/3 patients; IL28B-type did not influence outcome in these rapid responders. The major effect of this genetic variant was in patients who did not achieve a rapid response at week 4, where IL28B-type had a strong influence on the rate of SVR. A second point of contrast between this cohort and the genotype 1 North American cohort previously reported 14 was that the presence of a single C allele was noted to confer significant clinical benefit. In contrast, in genotype 1 HCV infection, the clinical benefit was more restricted to IL28B CC homozygotes 14.
Despite the association between IL28B-type and overall SVR, there was no significant association between the IL28B polymorphism and week 4 viral clearance, although RVR was numerically higher in CC and CT patients compared to TT patients. However, by week 8, viral clearance was clearly more common in CC and CT patients. We interpret this to mean that the IL28B polymorphism is associated with differential viral kinetics, similar to that observed in genotype 1, but that the different rate of decline between IL28B-types is attenuated, such that rates of viral clearance were not demonstrably different by week 4, but were significantly different at week 8. It is likely that quantitative measures of viral load may have been more sensitive for differentiating kinetics between patients with different IL28B-types, but unfortunately such measures were not available. We therefore acknowledge that the lack of HCV RNA decline evaluation represents a possible limitation of this study and that HCV RNA viral decline could have shown a better correlation with the IL28B genetic variant.
The study was not powered to formally evaluate the utility of IL28B-type for making decisions about selecting RVR patients for 12 weeks of therapy. Current guidelines recommend this approach for RVR patients with genotype 2/3 HCV infection and low viral load 10, 11. It is tempting to speculate that such treatment would be most suitable for CC patients. Although our data would be consistent with this being a subgroup of RVR patients most likely to achieve equivalent response rates, no significant difference was noted between 12 and 24 weeks of therapy in this cohort and we cannot draw firm conclusions. What appears more impressive is the potential role for IL28B genotyping in selecting non-RVR patients for standard 24 week therapy or more prolonged therapy. Prospective studies randomizing patients according to IL28B-type will be necessary to address both of these issues.
Of interest and as previously reported by Ge et al. in a genotype 1 HCV cohort 1, we also noted that the prevalence of the favourable C allele was lower in genotype 2/3 HCV-infected patients than in the non-HCV control population. This suggests that the T allele is associated with persistence, and is consistent with the recent observation that the IL28B CC-type is associated with spontaneous clearance following acute HCV infection 13, 15. The data therefore suggest that the role of IL28B variants in spontaneous clearance may be independent of HCV genotype.
Finally, the identification that genetic variation in the IL28B gene region is associated with pegIFN treatment outcome raises the possibility that IL28B might have therapeutic potential. IL28B (or IFN-lambda (␣)-3) is one of three members of the IFN-␣ family, first identified in 2003 16, 17. All 3 members signal via a common IFN- ␣ receptor, to trigger an IFN-stimulated gene response that overlaps considerably with the downstream signaling pathway of type 1 IFNs. Antiviral activity against both HCV and HBV has been demonstrated in vitro 18. Phase 1 studies investigating IL29 (IFN-␣-1) have recently confirmed an anti-HCV effect in genotype 1 non-responders 19. Phase II development in a genotype 1-naïve population is planned. The efficacy of IL29 in the setting of genotype 2/3 HCV is yet to be studied.
In conclusion, these findings highlight the importance of the interaction between HCV genotype and host genetic determinants in influencing treatment response. We have demonstrated that genetic variation in IL28B is associated with treatment response in patients infected with genotype 2/3 HCV. This effect is attenuated compared to previous reports in genotype 1 HCV, consistent with the recognized IFN-sensitivity of these genotypes, and also suggesting that key differences in the ability to evade innate antiviral immune responses are likely to exist between genotype 1 and genotype 2/3 HCV. IL28B- type was particularly important in patients who did not achieve RVR. Further prospective randomized studies are needed to investigate whether patients without RVR carrying the IL28B non-CC genotypes benefit from extended treatment duration.
Alessandra Mangia, Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Alexander J. Thompson, Duke Clinical Research Institute and Duke University Medical Center, Durham, NC, USA
Rosanna Santoro, Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Valeria Piazzolla, Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Hans L. Tillmann, Duke Clinical Research Institute and Duke University Medical Center, Durham, NC, USA
Keyur Patel, Duke Clinical Research Institute and Duke University Medical Center, Durham, NC, USA
Kevin V. Shianna, Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, NC, USA
Leonardo Mottola, Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Daniela Petruzzellis, Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Donato Bacca, Department of Internal Medicine, Hospital Castrano, Italy
Vito Carretta, Department of Internal Medicine Hospital Venosa, Italy
Nicola Minerva, Department of Internal Medicine, Hospital Canosa, Italy
David B. Goldstein, Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University, Durham, NC, USA
John G. McHutchison, Duke Clinical Research Institute and Duke University Medical Center, Durham, NC, USA
Received 17 February 2010; received in revised form 23 April 2010; accepted 25 May 2010. published online 04 June 2010.
Accepted Manuscript
Abstract
Background & Aims
Polymorphisms in the region of the interleukin (IL)28B gene on chromosome 19 have been associated with peginterferon-a (pegIFN)-induced clearance of genotype 1 hepatitis C virus (HCV); there are no data for patients with genotypes 2 or 3 (G2/3) HCV. We evaluated the effects of IL28B polymorphisms on response to treatment with pegIFN and ribavirin in a well-characterized cohort of G2/3 patients.
Methods
DNA was analyzed from 268 patients (Caucasian, G2=213, G3=55). Patients were randomly assigned to groups that received standard (24 weeks, SD24, n=68) or variable durations of therapy. Patients that received variable durations and had a rapid virological response (RVR) were treated for 12 weeks (VD12, n = 122); those without a RVR were treated for 24 weeks (VD24, n=78). IL28B genotypes (rs12979860) were analyzed for association with treatment response.
Results
The frequencies of the IL28B genotypes were: CC=37%, CT=48%, TT=15% ; 82% of patients with the CC genotype achieved a SVR, compared to 75% with the CT and 58% with the TT genotypes (P = 0.0046). Differences between IL28B genotypes were greatest among patients who failed to attain RVR (VD24 SVR rates: CC=87%, CT=67%, and TT=29%, P=0.0002). Among patients with RVRs (61%), the IL28B genotype was not associated with SVR (>70% for all IL28B genotypes). In a multi-variable logistic regression model, IL28B genotype predicted SVR (odds ratio=1.76; 95% confidence interval=1.16 - 2.7).
Conclusions
An IL28B polymorphism was associated with a SVR in patients infected with genotypes 2 or 3 HCV who did not achieve a RVR. Analysis of IL28B genotype might be used to guide treatment for these patients.
INTRODUCTION
Several viral and host-related factors determine the outcome of peginterferon-␣ (PegIFN) and ribavirin (RBV) treatment in patients with chronic hepatitis C virus (HCV) infection. In addition to viral genotype, serum HCV RNA level and stage of hepatic fibrosis, host genetic factors have recently been identified to influence treatment responsiveness in patients with chronic hepatitis C. Single nucleotide polymorphisms (SNPs) on a linkage disequilibrium block encompassing two interferon lambda genes on chromosome 19 have been strongly associated with response to pegIFN plus RBV combination treatment in three genome wide association studies of HCV genotype 1 infected patients 1-3. The strongest association signal to date has been for the SNP rs12979860 1. Adherent patients with the CC genotype of rs12979860 were more than twice as likely to respond to 48 weeks of treatment as compared to the non-CC genotypes1. Although the mechanism by which this genetic variant acts remains unclear, it is likely to influence innate antiviral immune responses. The influence of this genetic variation on response to shorter treatment courses in patients chronically infected with genotype 2 or 3 HCV is not known.
The current standard therapy for HCV genotype 2 and 3 infection is 24 weeks of pegIFN plus RBV, which cures approximately 80% of patients 4. In recent years, refinements to this regimen have been developed to minimize side effects and costs. In patients with low viral load at baseline who attain week 4 rapid virological response (RVR), 12 – 16 weeks of therapy is associated with rates of SVR that are comparable to those attained after a standard 24 weeks of treatment 5-7 . Although relapse rates may be somewhat higher with shorter therapy 8, the cost-effectiveness of this approach has been demonstrated 6, 9. Individualized therapy for patients with genotype 2/3 HCV infection according to RVR has recently been included in a number of European treatment guidelines 10, 11.
We have now investigated the relevance of IL28B genetic variation to treatment response in a well characterized cohort of European patients with genotype 2 or 3 HCV infection who were treated with pegIFN-alpha-2b and weight-based RBV for 12 or 24 weeks duration according to week 4 virological response, as previously published 5.
DISCUSSION
To our knowledge this is the first report of the role and relevance of the recently described IL28B genetic polymorphism to PegIFN and RBV treatment outcome in the setting of chronic infection with genotype 2 or 3 HCV. This unique cohort, from a prospectively performed landmark clinical trial 5, has allowed us to carefully evaluate the interaction between this genetic determinant and treatment response in patients who received a variable duration of therapy based upon week 4 virologic response.
The data indicate that the IL28B polymorphism is relevant to treatment outcome, although the effect size was attenuated in these genotype 2/ 3 infected European patients, compared to the original observation in North American patients with genotype 1 HCV infection (genotype 2/3: 1.76 [95% CI 1.16 – 2.66], Table 4A, vs genotype 1: OR 5.2 [95%CI 4.1 – 6.7] 14). The attenuation of overall effect size was largely due to the much higher rates of RVR that occurred in the genotype 2/3 patients; IL28B-type did not influence outcome in these rapid responders. The major effect of this genetic variant was in patients who did not achieve a rapid response at week 4, where IL28B-type had a strong influence on the rate of SVR. A second point of contrast between this cohort and the genotype 1 North American cohort previously reported 14 was that the presence of a single C allele was noted to confer significant clinical benefit. In contrast, in genotype 1 HCV infection, the clinical benefit was more restricted to IL28B CC homozygotes 14.
Despite the association between IL28B-type and overall SVR, there was no significant association between the IL28B polymorphism and week 4 viral clearance, although RVR was numerically higher in CC and CT patients compared to TT patients. However, by week 8, viral clearance was clearly more common in CC and CT patients. We interpret this to mean that the IL28B polymorphism is associated with differential viral kinetics, similar to that observed in genotype 1, but that the different rate of decline between IL28B-types is attenuated, such that rates of viral clearance were not demonstrably different by week 4, but were significantly different at week 8. It is likely that quantitative measures of viral load may have been more sensitive for differentiating kinetics between patients with different IL28B-types, but unfortunately such measures were not available. We therefore acknowledge that the lack of HCV RNA decline evaluation represents a possible limitation of this study and that HCV RNA viral decline could have shown a better correlation with the IL28B genetic variant.
The study was not powered to formally evaluate the utility of IL28B-type for making decisions about selecting RVR patients for 12 weeks of therapy. Current guidelines recommend this approach for RVR patients with genotype 2/3 HCV infection and low viral load 10, 11. It is tempting to speculate that such treatment would be most suitable for CC patients. Although our data would be consistent with this being a subgroup of RVR patients most likely to achieve equivalent response rates, no significant difference was noted between 12 and 24 weeks of therapy in this cohort and we cannot draw firm conclusions. What appears more impressive is the potential role for IL28B genotyping in selecting non-RVR patients for standard 24 week therapy or more prolonged therapy. Prospective studies randomizing patients according to IL28B-type will be necessary to address both of these issues.
Of interest and as previously reported by Ge et al. in a genotype 1 HCV cohort 1, we also noted that the prevalence of the favourable C allele was lower in genotype 2/3 HCV-infected patients than in the non-HCV control population. This suggests that the T allele is associated with persistence, and is consistent with the recent observation that the IL28B CC-type is associated with spontaneous clearance following acute HCV infection 13, 15. The data therefore suggest that the role of IL28B variants in spontaneous clearance may be independent of HCV genotype.
Finally, the identification that genetic variation in the IL28B gene region is associated with pegIFN treatment outcome raises the possibility that IL28B might have therapeutic potential. IL28B (or IFN-lambda (␣)-3) is one of three members of the IFN-␣ family, first identified in 2003 16, 17. All 3 members signal via a common IFN- ␣ receptor, to trigger an IFN-stimulated gene response that overlaps considerably with the downstream signaling pathway of type 1 IFNs. Antiviral activity against both HCV and HBV has been demonstrated in vitro 18. Phase 1 studies investigating IL29 (IFN-␣-1) have recently confirmed an anti-HCV effect in genotype 1 non-responders 19. Phase II development in a genotype 1-naïve population is planned. The efficacy of IL29 in the setting of genotype 2/3 HCV is yet to be studied.
In conclusion, these findings highlight the importance of the interaction between HCV genotype and host genetic determinants in influencing treatment response. We have demonstrated that genetic variation in IL28B is associated with treatment response in patients infected with genotype 2/3 HCV. This effect is attenuated compared to previous reports in genotype 1 HCV, consistent with the recognized IFN-sensitivity of these genotypes, and also suggesting that key differences in the ability to evade innate antiviral immune responses are likely to exist between genotype 1 and genotype 2/3 HCV. IL28B- type was particularly important in patients who did not achieve RVR. Further prospective randomized studies are needed to investigate whether patients without RVR carrying the IL28B non-CC genotypes benefit from extended treatment duration.
Low virological response and high relapse rates in hepatitis C genotype 1 patients
Low virological response and high relapse rates in hepatitis C genotype 1 patients with advanced fibrosis despite adequate therapeutic dosing - Jnl of Hepatology
from Jules: these data are compelling that earlier HCV therapy is better in general but of course other factors must also be considered. Ongoing HCV replication does damage including to the liver and perhaps in other ways as well.
"A total of 871 patients were enrolled, randomized (1:1) to induction and standard therapy, and received study drug (intention to treat analysis population)......Eligible subjects included treatment naïve adults aged 18–75years with chronic HCV genotype 1 infection and compensated liver disease (Child-Pugh Score <7)........These further analyses within the CHARIOT study provide robust evidence for the influence of fibrosis stage on treatment response. SVR was as high as 70% among patients with no fibrosis, declining in a step-wise fashion to rates of 31% for those with bridging fibrosis (n=97), and only 10% for those with cirrhosis (n=30)......the influence of fibrosis stage on PEG-IFN and ribavirin therapy outcomes in other studies has been based on two disease stage groupings only (generally advanced fibrosis and earlier disease) [2], [3], [18]. Further, key studies have not provided genotype-specific SVR by disease stage, including the pivotal studies of PEG-IFN and ribavirin therapy by Fried et al. [18] and Manns et al. [3]......A marked step-wise decline in SVR was evident by fibrosis stage: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001). Early virological responses were lower among F3/4 patients, including rapid virological response (RVR) (21% vs. 34% for F3/4 and F0–2, respectively) (p=0.0072), and the RVR positive predictive value was also lower (63% vs. 80%). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001)......A rapid virological response (RVR) was achieved in 25% and 18% of F3/4 patients on induction and standard therapy, respectively, compared to 39% and 28% in F0–2 patients...... A lower proportion of F3/4 patients reached undetectable HCV RNA by week 4 (21% vs. 34%) and week 8 (19% vs. 26%) (p<0.0001 for comparison of time to undetectable HCV RNA) (Fig. 3A). Furthermore, the SVR rates for each treatment response group were lower for F3/4 patients compared to F0–2 patients, including the rapid virological response group (week 4, 63% vs. 80%) (Fig. 3B). Thus, patients with advanced fibrosis had both slower initial viral decline and lower likelihood of SVR within each early treatment response group......
.....A potential explanation for our findings is the relationships between fibrosis stage, intrahepatic HCV RNA replication, and HCV clearance. Although patients with advanced fibrosis do not have higher serum HCV RNA levels, they have a higher percentage of hepatocytes with evidence of HCV RNA replication [19]. Viral kinetic studies have shown that patients with HCV genotype 1 and advanced fibrosis have slower second phase HCV RNA decline than those with less fibrosis [20], consistent with our week 4 and 8 response findings. Further, recent HCV modeling based on HCV genotype 1 patients indicates that patients with cirrhosis have lower SVR rates due to a higher percentage of HCV-infected hepatocytes [21]. An additional explanation would relate to potential immunological differences by extent of liver disease. Immunological characteristics including up-regulation of intrahepatic Th1-like cytokines and interferon-stimulated genes (ISGs) are known to influence both fibrosis progression and IFN-based treatment response [22], [23]. Finally, the recently reported association, between IL28B genetic polymorphisms and PEG-IFN/RBV treatment outcome in treatment naïve patients with chronic HCV genotype 1, indicates that host genetic characteristics are important for treatment responsiveness [24], [25]. If IL28B genetic polymorphisms associated with poor HCV treatment response are also found to be linked to liver disease progression, host genetic characteristics could explain the differential response by fibrosis stage......
......A further feature of the virological response patterns, between patients with and without advanced fibrosis, was the differential outcomes within similar virological response groupings. Patients with advanced fibrosis with initial undetectable HCV RNA at week 4, 8, 12, were less likely to achieve an SVR compared to those in the corresponding virological response group without advanced fibrosis. Among patients without advanced fibrosis and a RVR, the proportion with a SVR (PPV) was 80%, within the 77–90% RVR PPV range from other studies [26], [27], [28]. However, only 63% of patients with advanced fibrosis and RVR achieved a SVR. The high NPV of RVR for SVR among patients with advanced fibrosis (84%) makes extension of therapy a potential strategy for evaluation in this group. Extension of PEG-IFN and ribavirin therapy, from 48 to 72weeks among patients with HCV genotype 1 and non-RVR, has reduced relapse rates and increased SVR [29], [30], but data on this specific strategy among patients with advanced fibrosis is not available.....
.....Although combination therapy with PEG-IFN, ribavirin, and direct acting antivirals (DAA) such as protease or polymerase inhibitors has shown great promise in phase I and II evaluation, most of these trials have enrolled relatively few patients with advanced fibrosis (patients with established cirrhosis have generally been excluded) and disease stage-specific response data is not available [31], [32]. Pivotal studies among genotype 1 patients for the protease inhibitors telaprevir and boceprevir have included individuals with advanced fibrosis, therefore data on efficacy and safety in this sub-group is eagerly awaited."
Articles in Press
Low virological response and high relapse rates in hepatitis C genotype 1 patients with advanced fibrosis despite adequate therapeutic dosing
Journal of Hepatology
June 2010
Wendy S.C. Cheng1, Stuart K. Roberts2, Geoffrey McCaughan3, William Sievert4, Martin Weltman5, Darrell Crawford6, William Rawlinson7, Philippa S. Marks8, James Thommes9, Bishoy Rizkalla10, Motoko Yoshihara10, Gregory J Dore811, on behalf of the CHARIOT Study Group
1 Royal Perth Hospital, Perth, Australia, 2 Alfred Hospital, Melbourne, Australia, 3 Royal Prince Alfred Hospital, Sydney, Australia, 4 Monash Medical Centre and Monash University, Melbourne, Australia, 5 Nepean Hospital, Sydney, Australia, 6 Greenslopes Hospital, Brisbane, Australia, 7 SEALS Microbiology, Prince of Wales Hospital, Sydney, Australia, 8 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia, 9 Roche Products, Nutley, NJ, USA, 10 Roche Products, Sydney, Australia, 11 St. Vincent’s Hospital, Sydney, Australia
Received 12 November 2009; received in revised form 19 March 2010; accepted 11 April 2010. published online 23 June 2010.
Uncorrected Proof
ABSTRACT
Background & Aims
The impact of fibrosis stage on chronic hepatitis C virus (HCV) treatment response was explored in CHARIOT, a study of high dose peginterferon alfa-2a (PEG-IFNα-2a) induction therapy in treatment naïve genotype 1 infection.
Methods
Eight hundred and ninety-six patients were randomised 1:1 to 360μg (n=448) or 180μg (n=448) PEG-IFNα-2a weekly with RBV 1000–1200mg/day for 12weeks followed by 36weeks of 180μg PEG-IFNα-2a weekly plus RBV 1000–1200mg/day. Virological responses were assessed at week 4, 8, 12, 24, 48 (end of therapy), and 24weeks following therapy (sustained virological response, SVR). As previously reported, there was no significant difference in SVR in the induction (53%) and standard (50%) arms, therefore the pooled study population was used for analysis of SVR and relapse.
Results
A marked step-wise decline in SVR was evident by fibrosis stage: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001). Early virological responses were lower among F3/4 patients, including rapid virological response (RVR) (21% vs. 34% for F3/4 and F0–2, respectively) (p=0.0072), and the RVR positive predictive value was also lower (63% vs. 80%). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001). Cumulative PEG-IFNα-2a and ribavirin doses were similar among patients with F3/4 and F0–2 within treatment arms through week 4, 8, 12, and week 24.
Conclusion
Low virological response in hepatitis C genotype 1 patients with advanced fibrosis is not explained by inadequate cumulative PEG-IFN and ribavirin doses.
Introduction
Pegylated interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection achieves a sustained virological response (SVR) in 70–80% in genotype 2/3, but only 40–55% in genotype 1 infected patients [1], [2], [3]. Treatment response rates are particularly poor among patients with genotype 1 infection and advanced fibrosis (bridging fibrosis and compensated cirrhosis), with SVR rates of 15–40% [2], [3], [4], [5], [6], [7] reported from generally small study populations.
HCV-related cirrhosis is associated with a high risk of progression to hepatic decompensation, hepatocellular carcinoma (HCC), and liver-related mortality [8], [9], [10]. Although interferon-based HCV viral clearance is more difficult to achieve in patients with advanced fibrosis, there are clear benefits for those who do, with lower risk of progression to advanced liver disease complications [11], [12], [13], and regression of fibrosis in many [14], [15].
The CHARIOT trial was a large international randomized controlled trial of peginterferon (PEG-IFN) alfa-2a induction dosing in combination with ribavirin in treatment of naïve patients with chronic HCV genotype 1 infection [16]. Despite enhanced early virological responses, induction therapy provided no improvement in SVR (53% and 50% in induction and standard therapy arms, respectively). Preliminary analyses of the influence of fibrosis stage on treatment outcomes, following induction and standard therapy, demonstrated poor SVR rates among patients with advanced fibrosis (28% and 24%) compared to those with moderate (51% and 50%) and no or minimal fibrosis (64% and 60%) [16]. The aim of this analysis was to further evaluate the impact of fibrosis stage on treatment response within CHARIOT, including the predictive value of week 4, 8, and 12 responses, and virological relapse. In particular, the contribution of cumulative PEG-IFNα-2a and ribavirin dose to the lower virological responses observed in patients with advanced fibrosis was explored.
Results
Patient characteristics
A total of 871 patients were enrolled, randomized (1:1) to induction and standard therapy, and received study drug (intention to treat analysis population). Baseline liver histology was obtained in 625 of 871 patients (71.8%). Fibrosis stage was F3/4 in 127 patients (14.6%), F0–2 in 498 patients (57.2%), and missing in 246 patients (28.2%). F3/4 patients were older with higher body weight and baseline ALT levels compared to F0–2 patients (Table 1). All F3/4 patients had compensated liver disease (Child-Pugh Score 5 in 124 and 6 in 3 patients). The distribution of patient characteristics for those with biopsy staging were similar to those with missing staging, apart from a lower proportion of Caucasians (80% vs. 90%), and a higher baseline ALT level (median: 54 vs. 44U/L) in those with biopsy (Table 1). Laboratory markers of advanced fibrosis were similar among those with and without biopsy staging including AST/ALT ratio, serum albumin, serum total bilirubin, INR, and platelet count (Table 1). Only six (2.4%) patients with missing biopsy had a Child-Pugh Score of >5.
Virological responses
Induction therapy provided approximately 10% higher early virological responses including undetectable HCV RNA proportions at week 4, 8, and 12 for both F3/4 and F0–2 groups (Fig. 1). However, early virological responses were lower among F3/4 patients in both induction and standard groups compared to corresponding F0–2 patient groups; this difference was apparent by week 4. A rapid virological response (RVR) was achieved in 25% and 18% of F3/4 patients on induction and standard therapy, respectively, compared to 39% and 28% in F0–2 patients.
A similar disparity in virological response between F3/4 and F0–2 groups was seen at week 24 and week 48 (ETR), however, this disparity widened considerably by week 72, with SVR rates of 24–28% in F3/4 patients compared with 55–58% among F0–2 patients (p<0.0001) (Fig. 1).
The randomized groups were combined (given similar SVR rates) to explore the impact of individual fibrosis stage on treatment responses. A marked trend in SVR by fibrosis stage was evident with progressive declines in response with increasing fibrosis: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001) (Fig. 2A). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001) (Fig. 2B). Among patients without SVR, the percentage with non-response at week 12, virological breakthrough, and virological relapse was similar for patients with F0–2 (n=216; 27%, 36%, 37%, respectively) and patients with F3/4 (n=94; 30%, 28%, 42%, respectively).
The impact of early treatment response was further characterized in the overall population by determining SVR among fibrosis groups (F0–2, F3/4) within four mutually exclusive response groups based on the week of initial undetectable HCV RNA (week 4, 8, 12, 24). A lower proportion of F3/4 patients reached undetectable HCV RNA by week 4 (21% vs. 34%) and week 8 (19% vs. 26%) (p<0.0001 for comparison of time to undetectable HCV RNA) (Fig. 3A). Furthermore, the SVR rates for each treatment response group were lower for F3/4 patients compared to F0–2 patients, including the rapid virological response group (week 4, 63% vs. 80%) (Fig. 3B). Thus, patients with advanced fibrosis had both slower initial viral decline and lower likelihood of SVR within each early treatment response group.
In a multivariate analysis among patients with all baseline parameters available for inclusion (n=507), METAVIR fibrosis score was associated with SVR (p=0.0194). Adjusted odds ratios for SVR in comparisons with F4 patients were 8.9 (1.8–43.8), 6.3 (1.5–26.6), 5.7 (1.4–23.6), and 2.7 (0.6–11.5) for patients with F0, F1, F2, and F3, respectively.
Predictors of response
The predictive value of early virological response in determination of SVR was also examined, among fibrosis groups and randomized arms (Table 2). The positive predictive value (PPV) of RVR for SVR was lower among F3/4 patients in induction (60%) and standard (67%) arms compared to F0–2 patients (79% and 82%, respectively). Of note, the negative predictive value (NPV) of RVR for SVR was considerably higher among F3/4 patients (83–84%) compared to F0–2 patients (55–57%) (Table 2). Among F3/4 patients the PPV for SVR was lower and NPV higher at week 8. Also, the PPV of week 12 response for SVR, both EVR and cEVR, were considerably lower among F3/4 patients compared to F0–2 patients (Table 2), while NPV of EVR was 100% for all groups (note that patients in both arms without an EVR, continued therapy to week 24 then to week 48 if HCV RNA was undetectable at week 24).
Cumulative therapeutic dosing
The proportions of patients receiving >80% and >95% of planned PEG-IFNα-2a dose by week 12 and 24 were lower among patients on induction therapy, but similar among patients with F3/4 and F0–2 (Table 3). There was a marginally lower proportion with >95% cumulative dosage of PEG-IFNα-2a among F3/4 patients compared to F0–2 patients in the standard arm by week 12 (83.6% vs. 89.3%) and 24 (76.1% vs. 81.0%). The proportions with receipt of >80% and .95% of planned ribavirin dose were similar across randomized and fibrosis groupings, including >95% receipt by week 12 (F0–2: induction 80.1%, standard 83.9%; F3/4: induction 83.3%, standard 83.6%) and week 24 (F0–2: induction 74.6%, standard 74.8%; F3/4: induction 75.0%, standard 73.1%) (Table 3).
Methods
CHARIOT study population
The CHARIOT trial methods and patient population have been described in detail [16]. Eligible subjects included treatment naïve adults aged 18–75years with chronic HCV genotype 1 infection and compensated liver disease (Child-Pugh Score <7). Initial recruitment (in Australia from August 2004) excluded patients with cirrhosis. The protocol was revised in mid-2006 to allow inclusion of patients with normal serum ALT level and absence of liver biopsy staging of disease consistent with changes to Australian subsidized treatment requirements for serum ALT elevation (December 2005) and pre-treatment liver biopsy (April 2006). In addition, patients with compensated cirrhosis were able to enroll. Also, from mid-2006, recruitment commenced through several other countries (New Zealand, Thailand, Canada, Mexico, Argentina), with pre-treatment liver biopsy staging required in all these countries apart from New Zealand.
Patients meeting screening eligibility criteria were randomly assigned 1:1 to receive PEG-IFNα-2a either in an induction dose or standard dose regimen. The induction regimen consisted of 360μg of PEG-IFNα-2a weekly, for the first 12weeks, followed by 180μg of PEG-IFNα-2a weekly, for 36weeks and 1000/1200mg of ribavirin daily for 48weeks. The standard dose regimen involved 180μg of PEG-IFNα-2a weekly and 1000/1200mg of ribavirin daily for 48weeks. Patients in both arms without an early virological response (EVR) at week 12 continued therapy to week 24; patients with detectable HCV RNA at week 24 ceased therapy.
Cumulative exposure to PEG-IFNα-2a and ribavirin was determined by calculation of the percentage of planned dose received through week 4, 8, 12, 24, and 48. Reductions from maximum dose occurred through both clinician-directed dose modification and patient non-adherence, with adherence assessed via recording the injections and doses of PEG-IFNα-2a and ribavirin at each visit according to the patient’s detailed statements, and via documentation of drugs dispensed through pharmacy records.
Assessments and efficacy endpoints
Quantitative serum HCV RNA levels were measured at baseline and at weeks 4, 8, 12, 24, 48, and 72 (Roche Ampliprep/Cobas® TaqMan® HCV Test with a detection limit of 15IU/ml). Treatment response endpoints were defined as undetectable HCV RNA, including the primary endpoint at week 72, and were based on Taqman results below the level of detection (both undetectable and detectable <15IU/ml).
Liver biopsies were taken within 36months of treatment and scored by local pathologists. Fibrosis stage was classified according to the METAVIR system [17] as F0 (no), F1 (mild), F2 (moderate), F3 (severe), and F4 (cirrhosis). Advanced fibrosis included patients with either F3 or F4 fibrosis stage.
Statistical analysis
The intent-to-treat analysis population was defined as all patients randomized who received at least one dose of study medication. Percentages are calculated for categorical parameters. Means are calculated for the continuous variables. Area under the curve (AUC) of HCV RNA through week 24 is calculated and has been analyzed with F3/4 vs. F0–2 and treatment groups as factors in ANCOVA. A logistic regression analysis was conducted for SVR with METAVIR score as a prognosis factor. A multivariate logistic regression analysis was also conducted to evaluate the independent impact of fibrosis stage on SVR, with the following baseline variables included: treatment group, age, gender, race, body weight, METAVIR fibrosis score, screening HCV RNA level, subtype (1b or non-1b), ALT, AST/ALT ratio, hemoglobin, white blood cell count, platelet count, serum creatinine, serum albumin, total bilirubin, alkaline phosphatase, gamma-glutamyl transferase (GGT), and international normalized ratio (INR). Due to the exploratory nature of the analyses, no alpha-adjustments were applied to account for multiple significance testing.
from Jules: these data are compelling that earlier HCV therapy is better in general but of course other factors must also be considered. Ongoing HCV replication does damage including to the liver and perhaps in other ways as well.
"A total of 871 patients were enrolled, randomized (1:1) to induction and standard therapy, and received study drug (intention to treat analysis population)......Eligible subjects included treatment naïve adults aged 18–75years with chronic HCV genotype 1 infection and compensated liver disease (Child-Pugh Score <7)........These further analyses within the CHARIOT study provide robust evidence for the influence of fibrosis stage on treatment response. SVR was as high as 70% among patients with no fibrosis, declining in a step-wise fashion to rates of 31% for those with bridging fibrosis (n=97), and only 10% for those with cirrhosis (n=30)......the influence of fibrosis stage on PEG-IFN and ribavirin therapy outcomes in other studies has been based on two disease stage groupings only (generally advanced fibrosis and earlier disease) [2], [3], [18]. Further, key studies have not provided genotype-specific SVR by disease stage, including the pivotal studies of PEG-IFN and ribavirin therapy by Fried et al. [18] and Manns et al. [3]......A marked step-wise decline in SVR was evident by fibrosis stage: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001). Early virological responses were lower among F3/4 patients, including rapid virological response (RVR) (21% vs. 34% for F3/4 and F0–2, respectively) (p=0.0072), and the RVR positive predictive value was also lower (63% vs. 80%). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001)......A rapid virological response (RVR) was achieved in 25% and 18% of F3/4 patients on induction and standard therapy, respectively, compared to 39% and 28% in F0–2 patients...... A lower proportion of F3/4 patients reached undetectable HCV RNA by week 4 (21% vs. 34%) and week 8 (19% vs. 26%) (p<0.0001 for comparison of time to undetectable HCV RNA) (Fig. 3A). Furthermore, the SVR rates for each treatment response group were lower for F3/4 patients compared to F0–2 patients, including the rapid virological response group (week 4, 63% vs. 80%) (Fig. 3B). Thus, patients with advanced fibrosis had both slower initial viral decline and lower likelihood of SVR within each early treatment response group......
.....A potential explanation for our findings is the relationships between fibrosis stage, intrahepatic HCV RNA replication, and HCV clearance. Although patients with advanced fibrosis do not have higher serum HCV RNA levels, they have a higher percentage of hepatocytes with evidence of HCV RNA replication [19]. Viral kinetic studies have shown that patients with HCV genotype 1 and advanced fibrosis have slower second phase HCV RNA decline than those with less fibrosis [20], consistent with our week 4 and 8 response findings. Further, recent HCV modeling based on HCV genotype 1 patients indicates that patients with cirrhosis have lower SVR rates due to a higher percentage of HCV-infected hepatocytes [21]. An additional explanation would relate to potential immunological differences by extent of liver disease. Immunological characteristics including up-regulation of intrahepatic Th1-like cytokines and interferon-stimulated genes (ISGs) are known to influence both fibrosis progression and IFN-based treatment response [22], [23]. Finally, the recently reported association, between IL28B genetic polymorphisms and PEG-IFN/RBV treatment outcome in treatment naïve patients with chronic HCV genotype 1, indicates that host genetic characteristics are important for treatment responsiveness [24], [25]. If IL28B genetic polymorphisms associated with poor HCV treatment response are also found to be linked to liver disease progression, host genetic characteristics could explain the differential response by fibrosis stage......
......A further feature of the virological response patterns, between patients with and without advanced fibrosis, was the differential outcomes within similar virological response groupings. Patients with advanced fibrosis with initial undetectable HCV RNA at week 4, 8, 12, were less likely to achieve an SVR compared to those in the corresponding virological response group without advanced fibrosis. Among patients without advanced fibrosis and a RVR, the proportion with a SVR (PPV) was 80%, within the 77–90% RVR PPV range from other studies [26], [27], [28]. However, only 63% of patients with advanced fibrosis and RVR achieved a SVR. The high NPV of RVR for SVR among patients with advanced fibrosis (84%) makes extension of therapy a potential strategy for evaluation in this group. Extension of PEG-IFN and ribavirin therapy, from 48 to 72weeks among patients with HCV genotype 1 and non-RVR, has reduced relapse rates and increased SVR [29], [30], but data on this specific strategy among patients with advanced fibrosis is not available.....
.....Although combination therapy with PEG-IFN, ribavirin, and direct acting antivirals (DAA) such as protease or polymerase inhibitors has shown great promise in phase I and II evaluation, most of these trials have enrolled relatively few patients with advanced fibrosis (patients with established cirrhosis have generally been excluded) and disease stage-specific response data is not available [31], [32]. Pivotal studies among genotype 1 patients for the protease inhibitors telaprevir and boceprevir have included individuals with advanced fibrosis, therefore data on efficacy and safety in this sub-group is eagerly awaited."
Articles in Press
Low virological response and high relapse rates in hepatitis C genotype 1 patients with advanced fibrosis despite adequate therapeutic dosing
Journal of Hepatology
June 2010
Wendy S.C. Cheng1, Stuart K. Roberts2, Geoffrey McCaughan3, William Sievert4, Martin Weltman5, Darrell Crawford6, William Rawlinson7, Philippa S. Marks8, James Thommes9, Bishoy Rizkalla10, Motoko Yoshihara10, Gregory J Dore811, on behalf of the CHARIOT Study Group
1 Royal Perth Hospital, Perth, Australia, 2 Alfred Hospital, Melbourne, Australia, 3 Royal Prince Alfred Hospital, Sydney, Australia, 4 Monash Medical Centre and Monash University, Melbourne, Australia, 5 Nepean Hospital, Sydney, Australia, 6 Greenslopes Hospital, Brisbane, Australia, 7 SEALS Microbiology, Prince of Wales Hospital, Sydney, Australia, 8 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia, 9 Roche Products, Nutley, NJ, USA, 10 Roche Products, Sydney, Australia, 11 St. Vincent’s Hospital, Sydney, Australia
Received 12 November 2009; received in revised form 19 March 2010; accepted 11 April 2010. published online 23 June 2010.
Uncorrected Proof
ABSTRACT
Background & Aims
The impact of fibrosis stage on chronic hepatitis C virus (HCV) treatment response was explored in CHARIOT, a study of high dose peginterferon alfa-2a (PEG-IFNα-2a) induction therapy in treatment naïve genotype 1 infection.
Methods
Eight hundred and ninety-six patients were randomised 1:1 to 360μg (n=448) or 180μg (n=448) PEG-IFNα-2a weekly with RBV 1000–1200mg/day for 12weeks followed by 36weeks of 180μg PEG-IFNα-2a weekly plus RBV 1000–1200mg/day. Virological responses were assessed at week 4, 8, 12, 24, 48 (end of therapy), and 24weeks following therapy (sustained virological response, SVR). As previously reported, there was no significant difference in SVR in the induction (53%) and standard (50%) arms, therefore the pooled study population was used for analysis of SVR and relapse.
Results
A marked step-wise decline in SVR was evident by fibrosis stage: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001). Early virological responses were lower among F3/4 patients, including rapid virological response (RVR) (21% vs. 34% for F3/4 and F0–2, respectively) (p=0.0072), and the RVR positive predictive value was also lower (63% vs. 80%). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001). Cumulative PEG-IFNα-2a and ribavirin doses were similar among patients with F3/4 and F0–2 within treatment arms through week 4, 8, 12, and week 24.
Conclusion
Low virological response in hepatitis C genotype 1 patients with advanced fibrosis is not explained by inadequate cumulative PEG-IFN and ribavirin doses.
Introduction
Pegylated interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection achieves a sustained virological response (SVR) in 70–80% in genotype 2/3, but only 40–55% in genotype 1 infected patients [1], [2], [3]. Treatment response rates are particularly poor among patients with genotype 1 infection and advanced fibrosis (bridging fibrosis and compensated cirrhosis), with SVR rates of 15–40% [2], [3], [4], [5], [6], [7] reported from generally small study populations.
HCV-related cirrhosis is associated with a high risk of progression to hepatic decompensation, hepatocellular carcinoma (HCC), and liver-related mortality [8], [9], [10]. Although interferon-based HCV viral clearance is more difficult to achieve in patients with advanced fibrosis, there are clear benefits for those who do, with lower risk of progression to advanced liver disease complications [11], [12], [13], and regression of fibrosis in many [14], [15].
The CHARIOT trial was a large international randomized controlled trial of peginterferon (PEG-IFN) alfa-2a induction dosing in combination with ribavirin in treatment of naïve patients with chronic HCV genotype 1 infection [16]. Despite enhanced early virological responses, induction therapy provided no improvement in SVR (53% and 50% in induction and standard therapy arms, respectively). Preliminary analyses of the influence of fibrosis stage on treatment outcomes, following induction and standard therapy, demonstrated poor SVR rates among patients with advanced fibrosis (28% and 24%) compared to those with moderate (51% and 50%) and no or minimal fibrosis (64% and 60%) [16]. The aim of this analysis was to further evaluate the impact of fibrosis stage on treatment response within CHARIOT, including the predictive value of week 4, 8, and 12 responses, and virological relapse. In particular, the contribution of cumulative PEG-IFNα-2a and ribavirin dose to the lower virological responses observed in patients with advanced fibrosis was explored.
Results
Patient characteristics
A total of 871 patients were enrolled, randomized (1:1) to induction and standard therapy, and received study drug (intention to treat analysis population). Baseline liver histology was obtained in 625 of 871 patients (71.8%). Fibrosis stage was F3/4 in 127 patients (14.6%), F0–2 in 498 patients (57.2%), and missing in 246 patients (28.2%). F3/4 patients were older with higher body weight and baseline ALT levels compared to F0–2 patients (Table 1). All F3/4 patients had compensated liver disease (Child-Pugh Score 5 in 124 and 6 in 3 patients). The distribution of patient characteristics for those with biopsy staging were similar to those with missing staging, apart from a lower proportion of Caucasians (80% vs. 90%), and a higher baseline ALT level (median: 54 vs. 44U/L) in those with biopsy (Table 1). Laboratory markers of advanced fibrosis were similar among those with and without biopsy staging including AST/ALT ratio, serum albumin, serum total bilirubin, INR, and platelet count (Table 1). Only six (2.4%) patients with missing biopsy had a Child-Pugh Score of >5.
Virological responses
Induction therapy provided approximately 10% higher early virological responses including undetectable HCV RNA proportions at week 4, 8, and 12 for both F3/4 and F0–2 groups (Fig. 1). However, early virological responses were lower among F3/4 patients in both induction and standard groups compared to corresponding F0–2 patient groups; this difference was apparent by week 4. A rapid virological response (RVR) was achieved in 25% and 18% of F3/4 patients on induction and standard therapy, respectively, compared to 39% and 28% in F0–2 patients.
A similar disparity in virological response between F3/4 and F0–2 groups was seen at week 24 and week 48 (ETR), however, this disparity widened considerably by week 72, with SVR rates of 24–28% in F3/4 patients compared with 55–58% among F0–2 patients (p<0.0001) (Fig. 1).
The randomized groups were combined (given similar SVR rates) to explore the impact of individual fibrosis stage on treatment responses. A marked trend in SVR by fibrosis stage was evident with progressive declines in response with increasing fibrosis: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001) (Fig. 2A). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001) (Fig. 2B). Among patients without SVR, the percentage with non-response at week 12, virological breakthrough, and virological relapse was similar for patients with F0–2 (n=216; 27%, 36%, 37%, respectively) and patients with F3/4 (n=94; 30%, 28%, 42%, respectively).
The impact of early treatment response was further characterized in the overall population by determining SVR among fibrosis groups (F0–2, F3/4) within four mutually exclusive response groups based on the week of initial undetectable HCV RNA (week 4, 8, 12, 24). A lower proportion of F3/4 patients reached undetectable HCV RNA by week 4 (21% vs. 34%) and week 8 (19% vs. 26%) (p<0.0001 for comparison of time to undetectable HCV RNA) (Fig. 3A). Furthermore, the SVR rates for each treatment response group were lower for F3/4 patients compared to F0–2 patients, including the rapid virological response group (week 4, 63% vs. 80%) (Fig. 3B). Thus, patients with advanced fibrosis had both slower initial viral decline and lower likelihood of SVR within each early treatment response group.
In a multivariate analysis among patients with all baseline parameters available for inclusion (n=507), METAVIR fibrosis score was associated with SVR (p=0.0194). Adjusted odds ratios for SVR in comparisons with F4 patients were 8.9 (1.8–43.8), 6.3 (1.5–26.6), 5.7 (1.4–23.6), and 2.7 (0.6–11.5) for patients with F0, F1, F2, and F3, respectively.
Predictors of response
The predictive value of early virological response in determination of SVR was also examined, among fibrosis groups and randomized arms (Table 2). The positive predictive value (PPV) of RVR for SVR was lower among F3/4 patients in induction (60%) and standard (67%) arms compared to F0–2 patients (79% and 82%, respectively). Of note, the negative predictive value (NPV) of RVR for SVR was considerably higher among F3/4 patients (83–84%) compared to F0–2 patients (55–57%) (Table 2). Among F3/4 patients the PPV for SVR was lower and NPV higher at week 8. Also, the PPV of week 12 response for SVR, both EVR and cEVR, were considerably lower among F3/4 patients compared to F0–2 patients (Table 2), while NPV of EVR was 100% for all groups (note that patients in both arms without an EVR, continued therapy to week 24 then to week 48 if HCV RNA was undetectable at week 24).
Cumulative therapeutic dosing
The proportions of patients receiving >80% and >95% of planned PEG-IFNα-2a dose by week 12 and 24 were lower among patients on induction therapy, but similar among patients with F3/4 and F0–2 (Table 3). There was a marginally lower proportion with >95% cumulative dosage of PEG-IFNα-2a among F3/4 patients compared to F0–2 patients in the standard arm by week 12 (83.6% vs. 89.3%) and 24 (76.1% vs. 81.0%). The proportions with receipt of >80% and .95% of planned ribavirin dose were similar across randomized and fibrosis groupings, including >95% receipt by week 12 (F0–2: induction 80.1%, standard 83.9%; F3/4: induction 83.3%, standard 83.6%) and week 24 (F0–2: induction 74.6%, standard 74.8%; F3/4: induction 75.0%, standard 73.1%) (Table 3).
Methods
CHARIOT study population
The CHARIOT trial methods and patient population have been described in detail [16]. Eligible subjects included treatment naïve adults aged 18–75years with chronic HCV genotype 1 infection and compensated liver disease (Child-Pugh Score <7). Initial recruitment (in Australia from August 2004) excluded patients with cirrhosis. The protocol was revised in mid-2006 to allow inclusion of patients with normal serum ALT level and absence of liver biopsy staging of disease consistent with changes to Australian subsidized treatment requirements for serum ALT elevation (December 2005) and pre-treatment liver biopsy (April 2006). In addition, patients with compensated cirrhosis were able to enroll. Also, from mid-2006, recruitment commenced through several other countries (New Zealand, Thailand, Canada, Mexico, Argentina), with pre-treatment liver biopsy staging required in all these countries apart from New Zealand.
Patients meeting screening eligibility criteria were randomly assigned 1:1 to receive PEG-IFNα-2a either in an induction dose or standard dose regimen. The induction regimen consisted of 360μg of PEG-IFNα-2a weekly, for the first 12weeks, followed by 180μg of PEG-IFNα-2a weekly, for 36weeks and 1000/1200mg of ribavirin daily for 48weeks. The standard dose regimen involved 180μg of PEG-IFNα-2a weekly and 1000/1200mg of ribavirin daily for 48weeks. Patients in both arms without an early virological response (EVR) at week 12 continued therapy to week 24; patients with detectable HCV RNA at week 24 ceased therapy.
Cumulative exposure to PEG-IFNα-2a and ribavirin was determined by calculation of the percentage of planned dose received through week 4, 8, 12, 24, and 48. Reductions from maximum dose occurred through both clinician-directed dose modification and patient non-adherence, with adherence assessed via recording the injections and doses of PEG-IFNα-2a and ribavirin at each visit according to the patient’s detailed statements, and via documentation of drugs dispensed through pharmacy records.
Assessments and efficacy endpoints
Quantitative serum HCV RNA levels were measured at baseline and at weeks 4, 8, 12, 24, 48, and 72 (Roche Ampliprep/Cobas® TaqMan® HCV Test with a detection limit of 15IU/ml). Treatment response endpoints were defined as undetectable HCV RNA, including the primary endpoint at week 72, and were based on Taqman results below the level of detection (both undetectable and detectable <15IU/ml).
Liver biopsies were taken within 36months of treatment and scored by local pathologists. Fibrosis stage was classified according to the METAVIR system [17] as F0 (no), F1 (mild), F2 (moderate), F3 (severe), and F4 (cirrhosis). Advanced fibrosis included patients with either F3 or F4 fibrosis stage.
Statistical analysis
The intent-to-treat analysis population was defined as all patients randomized who received at least one dose of study medication. Percentages are calculated for categorical parameters. Means are calculated for the continuous variables. Area under the curve (AUC) of HCV RNA through week 24 is calculated and has been analyzed with F3/4 vs. F0–2 and treatment groups as factors in ANCOVA. A logistic regression analysis was conducted for SVR with METAVIR score as a prognosis factor. A multivariate logistic regression analysis was also conducted to evaluate the independent impact of fibrosis stage on SVR, with the following baseline variables included: treatment group, age, gender, race, body weight, METAVIR fibrosis score, screening HCV RNA level, subtype (1b or non-1b), ALT, AST/ALT ratio, hemoglobin, white blood cell count, platelet count, serum creatinine, serum albumin, total bilirubin, alkaline phosphatase, gamma-glutamyl transferase (GGT), and international normalized ratio (INR). Due to the exploratory nature of the analyses, no alpha-adjustments were applied to account for multiple significance testing.
FDA Approves Rapid Test for Antibodies to Hepatitis C Virus
FDA NEWS RELEASE
For Immediate Release: June 25, 2010
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
FDA Approves Rapid Test for Antibodies to Hepatitis C Virus
The U.S. Food and Drug Administration today announced approval of the first rapid blood test for antibodies to the hepatitis C virus (HCV) for individuals 15 years and older.
The OraQuick HCV Rapid Antibody Test is used to test individuals who are at risk for infection with HCV and people with signs or symptoms of hepatitis. HCV is transmitted through exposure to infected blood, which, for example, can occur during intravenous drug use. The virus can also be transferred from an infected mother to her child. Hepatitis C can lead to liver inflammation and dysfunction and, over time, to liver disease and liver cancer.
OraQuick is a test strip and does not require an instrument for diagnosis. It takes about 20 minutes to obtain results from the test.
“Approval of OraQuick means that more patients can be notified of their HCV infection faster so that they can consult with their physicians for appropriate health measures,” said Jeffrey Shuren, M.D., J.D., director of the FDA?s Center for Devices and Radiological Health. “Getting faster treatment is an important public health step to control this dangerous disease.”
OraQuick is not approved for HCV screening of the general population.
According to the U.S. Centers for Disease Control and Prevention, there are approximately 3.2 million people in the United States chronically infected with HCV and each year, about 17,000 people are newly infected. Chronic HCV infection is a leading reason for a liver transplants in the United States and HCV is associated with an estimated 12,000 deaths annually. Approximately 75 to 85 percent of people who become infected with the hepatitis C virus develop chronic infection.
OraQuick is manufactured by Bethlehem, Penn.-based OraSure Technologies Inc.
For Immediate Release: June 25, 2010
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
FDA Approves Rapid Test for Antibodies to Hepatitis C Virus
The U.S. Food and Drug Administration today announced approval of the first rapid blood test for antibodies to the hepatitis C virus (HCV) for individuals 15 years and older.
The OraQuick HCV Rapid Antibody Test is used to test individuals who are at risk for infection with HCV and people with signs or symptoms of hepatitis. HCV is transmitted through exposure to infected blood, which, for example, can occur during intravenous drug use. The virus can also be transferred from an infected mother to her child. Hepatitis C can lead to liver inflammation and dysfunction and, over time, to liver disease and liver cancer.
OraQuick is a test strip and does not require an instrument for diagnosis. It takes about 20 minutes to obtain results from the test.
“Approval of OraQuick means that more patients can be notified of their HCV infection faster so that they can consult with their physicians for appropriate health measures,” said Jeffrey Shuren, M.D., J.D., director of the FDA?s Center for Devices and Radiological Health. “Getting faster treatment is an important public health step to control this dangerous disease.”
OraQuick is not approved for HCV screening of the general population.
According to the U.S. Centers for Disease Control and Prevention, there are approximately 3.2 million people in the United States chronically infected with HCV and each year, about 17,000 people are newly infected. Chronic HCV infection is a leading reason for a liver transplants in the United States and HCV is associated with an estimated 12,000 deaths annually. Approximately 75 to 85 percent of people who become infected with the hepatitis C virus develop chronic infection.
OraQuick is manufactured by Bethlehem, Penn.-based OraSure Technologies Inc.
OraSure gets FDA nod for hepatitis C test
OraSure gets FDA nod for hepatitis C test, shares up
Fri Jun 25, 2010 1:10pm EDT
* Says partner Merck to provide promotional support
* Shares up as much as 16 pct (Adds analyst comments, details, updates share movement)
By Anand Basu
BANGALORE, June 25 (Reuters) - OraSure Technologies Inc (OSUR.O) said it received U.S. regulatory approval to market a hepatitis C virus (HCV) test, OraQuick, sending its shares up 16 percent.
The approval of the device to detect HCV antibodies in unmodified blood specimen collected from the vein raises hopes of the test getting the nod for multiple specimen types such as oral fluid and fingerstick whole blood sample types.
"It is the first step of the approval process. The main market is going to be the oral fluid test," said Needham & Co analyst Sameer Harish.
Oral fluid test is usually preferred by patients over whole blood test as specimens can be collected easily and don't require blood samples.
Harish, who has a "buy" rating on OraSure shares, expects the FDA to approve the oral fluid HCV test this year.
OraSure already has one FDA approved HIV test, OraQuick Advance Rapid, in the U.S. market for detecting antibodies to HIV-1 and HIV-2.
Last year, the U.S. Food and Drug Administration declined to approve the company's HCV rapid antibody test OraQuick on concerns of potential bias in data interpretation. [ID:nBNG12307]
In the United States there are about 4.1 million people, or 1.6 percent of the population, who have been infected with HCV, the company said.
The company, which has partnered with Merck & Co (MRK.N) for the HCV test, said Merck will provide promotional support, including detailing the test in the physicians' office market.
Shares of the company were up 5 percent at $5.11 Friday afternoon on Nasdaq. They earlier touched a high of $5.63.
------------------
press release
June 25, 2010, 10:35 a.m. EDT ·
OraSure Technologies Receives FDA Approval for OraQuick(R) HCV Rapid Test, the First Rapid HCV Test Approved for Sale in the U.S.
BETHLEHEM, Pa., Jun 25, 2010 (GlobeNewswire via COMTEX) -- OraSure Technologies, Inc. /quotes/comstock/15*!osur/quotes/nls/osur (OSUR 4.97, +0.12, +2.47%) announced today that its OraQuick(R) Hepatitis C ("HCV") Rapid Antibody Test has been approved by the U.S. Food and Drug Administration ("FDA") for use in detecting HCV antibodies in venous whole blood specimens, making it the first rapid HCV test approved by the FDA for use in the United States.
"The OraQuick HCV test efficiently identifies previously undiagnosed HCV infected individuals who are at risk," said Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF, University of Miami School of Medicine. "We at the University of Miami found this test to be user-friendly, practical and an important tool for rapid HCV antibody detection."
"We believe that the OraQuick(R) HCV Rapid Antibody Test, with its simplicity and speed, will be a critical tool in identifying more at risk individuals infected with hepatitis C in the U.S., and thus represents a significant market opportunity," said Douglas A. Michels, President and Chief Executive Officer of OraSure Technologies. "Obtaining FDA approval of our OraQuick(R) HCV Rapid Antibody Test for venous whole blood represents a major milestone for our Company."
OraQuick(R) HCV is the only rapid, point-of-care test for the detection of antibodies to the hepatitis C virus in venous whole blood specimens that is approved by the FDA. The test, which utilizes the OraQuick(R) technology platform, provides results in 20 minutes. The OraQuick(R) HCV Rapid Antibody Test is the latest rapid test manufactured by OraSure to receive FDA approval. OraSure had previously received FDA approval for its OraQuick ADVANCE(R) Rapid HIV-1/2 Antibody Test for use with oral fluid, fingerstick and venous whole blood and plasma samples.
In the U.S., there are an estimated 4.1 million Americans, or 1.6 percent of the population, that are or have been infected with HCV. According to the Centers for Disease Control and Prevention ("CDC"), new infections in the U.S. are estimated at approximately 20,000 per year. On a worldwide basis, there are an estimated 180 million people who are chronically infected with HCV, with an estimated 3 to 4 million individuals newly infected each year.
According to the World Health Organization, most cases of HCV infection are currently undiagnosed and up to 80 percent of HCV-positive individuals show no signs or symptoms.
In December 2009, the Company received the CE mark for its OraQuick HCV Rapid Antibody Test for use with oral fluid, whole blood, serum and plasma specimens. The CE mark was required in order to sell the product in the European Union.
As previously announced, OraSure has entered into agreements with Merck & Co. (through its predecessor Schering Plough Corporation) to collaborate on the development and promotion of the OraQuick(R) HCV test. Under the terms of these agreements, the Company has been and will be reimbursed by Merck for a portion of its costs to develop the test and obtain regulatory approvals. Additionally, Merck will provide promotional support, including detailing the test in the physicians' office market in those countries in which the Company has obtained approval.
About OraSure Technologies
OraSure Technologies develops, manufactures and markets oral fluid specimen collection devices using proprietary oral fluid technologies, diagnostic products including immunoassays and other in vitro diagnostic tests, and other medical devices. These products are sold in the United States as well as internationally to various clinical laboratories, hospitals, clinics, community-based organizations and other public health organizations, distributors, government agencies, physicians' offices, and commercial and industrial entities.
OraSure Technologies is the leading supplier of oral-fluid testing solutions for drugs of abuse and for the detection of antibodies to HIV.
For more information on the Company, please go to www.orasure.com.
The OraSure Technologies, Inc. logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=6440
Fri Jun 25, 2010 1:10pm EDT
* Says partner Merck to provide promotional support
* Shares up as much as 16 pct (Adds analyst comments, details, updates share movement)
By Anand Basu
BANGALORE, June 25 (Reuters) - OraSure Technologies Inc (OSUR.O) said it received U.S. regulatory approval to market a hepatitis C virus (HCV) test, OraQuick, sending its shares up 16 percent.
The approval of the device to detect HCV antibodies in unmodified blood specimen collected from the vein raises hopes of the test getting the nod for multiple specimen types such as oral fluid and fingerstick whole blood sample types.
"It is the first step of the approval process. The main market is going to be the oral fluid test," said Needham & Co analyst Sameer Harish.
Oral fluid test is usually preferred by patients over whole blood test as specimens can be collected easily and don't require blood samples.
Harish, who has a "buy" rating on OraSure shares, expects the FDA to approve the oral fluid HCV test this year.
OraSure already has one FDA approved HIV test, OraQuick Advance Rapid, in the U.S. market for detecting antibodies to HIV-1 and HIV-2.
Last year, the U.S. Food and Drug Administration declined to approve the company's HCV rapid antibody test OraQuick on concerns of potential bias in data interpretation. [ID:nBNG12307]
In the United States there are about 4.1 million people, or 1.6 percent of the population, who have been infected with HCV, the company said.
The company, which has partnered with Merck & Co (MRK.N) for the HCV test, said Merck will provide promotional support, including detailing the test in the physicians' office market.
Shares of the company were up 5 percent at $5.11 Friday afternoon on Nasdaq. They earlier touched a high of $5.63.
------------------
press release
June 25, 2010, 10:35 a.m. EDT ·
OraSure Technologies Receives FDA Approval for OraQuick(R) HCV Rapid Test, the First Rapid HCV Test Approved for Sale in the U.S.
BETHLEHEM, Pa., Jun 25, 2010 (GlobeNewswire via COMTEX) -- OraSure Technologies, Inc. /quotes/comstock/15*!osur/quotes/nls/osur (OSUR 4.97, +0.12, +2.47%) announced today that its OraQuick(R) Hepatitis C ("HCV") Rapid Antibody Test has been approved by the U.S. Food and Drug Administration ("FDA") for use in detecting HCV antibodies in venous whole blood specimens, making it the first rapid HCV test approved by the FDA for use in the United States.
"The OraQuick HCV test efficiently identifies previously undiagnosed HCV infected individuals who are at risk," said Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF, University of Miami School of Medicine. "We at the University of Miami found this test to be user-friendly, practical and an important tool for rapid HCV antibody detection."
"We believe that the OraQuick(R) HCV Rapid Antibody Test, with its simplicity and speed, will be a critical tool in identifying more at risk individuals infected with hepatitis C in the U.S., and thus represents a significant market opportunity," said Douglas A. Michels, President and Chief Executive Officer of OraSure Technologies. "Obtaining FDA approval of our OraQuick(R) HCV Rapid Antibody Test for venous whole blood represents a major milestone for our Company."
OraQuick(R) HCV is the only rapid, point-of-care test for the detection of antibodies to the hepatitis C virus in venous whole blood specimens that is approved by the FDA. The test, which utilizes the OraQuick(R) technology platform, provides results in 20 minutes. The OraQuick(R) HCV Rapid Antibody Test is the latest rapid test manufactured by OraSure to receive FDA approval. OraSure had previously received FDA approval for its OraQuick ADVANCE(R) Rapid HIV-1/2 Antibody Test for use with oral fluid, fingerstick and venous whole blood and plasma samples.
In the U.S., there are an estimated 4.1 million Americans, or 1.6 percent of the population, that are or have been infected with HCV. According to the Centers for Disease Control and Prevention ("CDC"), new infections in the U.S. are estimated at approximately 20,000 per year. On a worldwide basis, there are an estimated 180 million people who are chronically infected with HCV, with an estimated 3 to 4 million individuals newly infected each year.
According to the World Health Organization, most cases of HCV infection are currently undiagnosed and up to 80 percent of HCV-positive individuals show no signs or symptoms.
In December 2009, the Company received the CE mark for its OraQuick HCV Rapid Antibody Test for use with oral fluid, whole blood, serum and plasma specimens. The CE mark was required in order to sell the product in the European Union.
As previously announced, OraSure has entered into agreements with Merck & Co. (through its predecessor Schering Plough Corporation) to collaborate on the development and promotion of the OraQuick(R) HCV test. Under the terms of these agreements, the Company has been and will be reimbursed by Merck for a portion of its costs to develop the test and obtain regulatory approvals. Additionally, Merck will provide promotional support, including detailing the test in the physicians' office market in those countries in which the Company has obtained approval.
About OraSure Technologies
OraSure Technologies develops, manufactures and markets oral fluid specimen collection devices using proprietary oral fluid technologies, diagnostic products including immunoassays and other in vitro diagnostic tests, and other medical devices. These products are sold in the United States as well as internationally to various clinical laboratories, hospitals, clinics, community-based organizations and other public health organizations, distributors, government agencies, physicians' offices, and commercial and industrial entities.
OraSure Technologies is the leading supplier of oral-fluid testing solutions for drugs of abuse and for the detection of antibodies to HIV.
For more information on the Company, please go to www.orasure.com.
The OraSure Technologies, Inc. logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=6440
5th International Workshop on Hepatitis C
http://natap.org/
_______________________________________________
from jules: I just returned from 3 days in Boston at the HCV Pharmacology & Resistance in New HCV Compounds Workshop. There was quite a lot of controversy about how drug resistance will look related to the new oral HCV drugs, the key question being when patients fail will mutations prevent response to future use of the same class of drugs or in fact reusing the same drug. For people familiar with HIV drug resistance this statement may sound strange because in HIV mutations once developed persist forever and prevent use of the same class of drugs except of course until effective drugs were developed that specifically were developed to suppress resistant virus like for example darunavir & kaletra. But in HCV it appears now that it may be different but we do not know yet exactly what will develop so there is a lot of controversy. For example if a patient fails an HCV protease inhibitor & mutations develop will these mutations prevent a response to another protease inhibitor or the same one used 3 years later after perhaps the mutations fade, because some researchers say these mutations are not archived like in HIV. We do not know what will happen & this is an important question. Nonetheless in 2011 it is expected that 2 HCV orally administered protease inhibitors will be FDA approved to be used in triple drug combination therapy each one separately with peginterferon plus ribavirin. Behind this a re another 20+ orally administered HCV drugs, which are expected to be equally effective in whits & african-americans, in treatment-naives and treatment-experienced, except of course the background therapy of peg/rbv will not be as effective in treatment-experienced prior nonresponders and this is a very important point to bear in mind in deciding when to begin therapy as in the future standard of care therapy is expected to be 2, 3 or 4 oral drugs in combination with or without peg/rbv which offer to everyone in the USA the opportunity to be cured, unless of course if a patient's HCV disease is so far progressed they are too sick to take the medications. Here are initial reports from the conference and more reports will be forthcoming.
5th International Workshop on Hepatitis C
Resistance and New Compounds
24-25 June 2010, Boston, MA USA
Ch ronic HCV Infection: How Does Maturation of the HCV Infected Patient Population Impact Drug Development - Gary Davis MD - (06/25/10)
Aging of Hepatitis C Virus (HCV)-Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression
Gastroenterology Feb 2010
HCC in persons older than the age of 65 years with HCV infection has doubled during the last several years....
Currently, only a small proportion of those with CH-C are aware of their infection and, of these, just 10% to 27% are offered treatment.....
the proportion of cases with advanced fibrosis will continue to rise during the next 2 decades (Cirrhosis accounted for just 5% of all cases (diagnosed and undiagnosed) of CH-C in 1989, 10% in 1998, and 20% in 2006, the proportion with c irrhosis is projected to reach 24.8% in 2010, 37.2% in 2020, and 44.9% in 2030).....
critical to identify infected persons and treat their disease before advanced fibrosis or liver failure ensues
1. Aging of Hepatitis C Virus (HCV)-Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression - (03/11/10)
Implications of host polymorphism IL28b for drug development and patient care - Mark Sulkowski MD - (06/25/10)
1. Amino acid substitution in HCV core region and genetic variation ne ar IL28B gene predict viral response to telaprevir with peginterferon and ribavirin - (05/03/10)
Hepatology - Accepted Preprint
26 Mar 2010
According to the genetic variation in rs12979860, sustained virological response was achieved by 83.8% (31 of 37 patients), 34.5% (10 of 29 patients), and 0% (0 of 2 patients), in patients with genotype CC, CT, and TT, respectively. Thus, a significantly higher proportion of patients with genotype CC (83.8%) showed sustained virological response than that of patients who showed genotype non-CC (32.3%) (Figure 2, P<0.0 01) (Table 2).
1. Hepatitis C Treatment in an Urban Population -
SVR rate for genotype 1 hispanics in this study is 11% and 30% for genotype 2 and 14% for African-Americans with genotype 1
The 5th International Workshop on
Clinical Pharmacology of Hepatitis Therapy
Boston, MA June 23-24, 2010
* Regulatory Requirements for Early Clinical Testing of Novel HCV Antiviral Drugs: FDA Perspective, Jeff Murray, M.D., M.P.H. FDA, Division of Antiviral Products - (06/25/10)
* A European Perspective: EMA and his critical standpoint, Prof. Jean-Michel Pawlotsky, MD, PhD - (06/23/10)
_______________________________________________
from jules: I just returned from 3 days in Boston at the HCV Pharmacology & Resistance in New HCV Compounds Workshop. There was quite a lot of controversy about how drug resistance will look related to the new oral HCV drugs, the key question being when patients fail will mutations prevent response to future use of the same class of drugs or in fact reusing the same drug. For people familiar with HIV drug resistance this statement may sound strange because in HIV mutations once developed persist forever and prevent use of the same class of drugs except of course until effective drugs were developed that specifically were developed to suppress resistant virus like for example darunavir & kaletra. But in HCV it appears now that it may be different but we do not know yet exactly what will develop so there is a lot of controversy. For example if a patient fails an HCV protease inhibitor & mutations develop will these mutations prevent a response to another protease inhibitor or the same one used 3 years later after perhaps the mutations fade, because some researchers say these mutations are not archived like in HIV. We do not know what will happen & this is an important question. Nonetheless in 2011 it is expected that 2 HCV orally administered protease inhibitors will be FDA approved to be used in triple drug combination therapy each one separately with peginterferon plus ribavirin. Behind this a re another 20+ orally administered HCV drugs, which are expected to be equally effective in whits & african-americans, in treatment-naives and treatment-experienced, except of course the background therapy of peg/rbv will not be as effective in treatment-experienced prior nonresponders and this is a very important point to bear in mind in deciding when to begin therapy as in the future standard of care therapy is expected to be 2, 3 or 4 oral drugs in combination with or without peg/rbv which offer to everyone in the USA the opportunity to be cured, unless of course if a patient's HCV disease is so far progressed they are too sick to take the medications. Here are initial reports from the conference and more reports will be forthcoming.
5th International Workshop on Hepatitis C
Resistance and New Compounds
24-25 June 2010, Boston, MA USA
Ch ronic HCV Infection: How Does Maturation of the HCV Infected Patient Population Impact Drug Development - Gary Davis MD - (06/25/10)
Aging of Hepatitis C Virus (HCV)-Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression
Gastroenterology Feb 2010
HCC in persons older than the age of 65 years with HCV infection has doubled during the last several years....
Currently, only a small proportion of those with CH-C are aware of their infection and, of these, just 10% to 27% are offered treatment.....
the proportion of cases with advanced fibrosis will continue to rise during the next 2 decades (Cirrhosis accounted for just 5% of all cases (diagnosed and undiagnosed) of CH-C in 1989, 10% in 1998, and 20% in 2006, the proportion with c irrhosis is projected to reach 24.8% in 2010, 37.2% in 2020, and 44.9% in 2030).....
critical to identify infected persons and treat their disease before advanced fibrosis or liver failure ensues
1. Aging of Hepatitis C Virus (HCV)-Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression - (03/11/10)
Implications of host polymorphism IL28b for drug development and patient care - Mark Sulkowski MD - (06/25/10)
1. Amino acid substitution in HCV core region and genetic variation ne ar IL28B gene predict viral response to telaprevir with peginterferon and ribavirin - (05/03/10)
Hepatology - Accepted Preprint
26 Mar 2010
According to the genetic variation in rs12979860, sustained virological response was achieved by 83.8% (31 of 37 patients), 34.5% (10 of 29 patients), and 0% (0 of 2 patients), in patients with genotype CC, CT, and TT, respectively. Thus, a significantly higher proportion of patients with genotype CC (83.8%) showed sustained virological response than that of patients who showed genotype non-CC (32.3%) (Figure 2, P<0.0 01) (Table 2).
1. Hepatitis C Treatment in an Urban Population -
SVR rate for genotype 1 hispanics in this study is 11% and 30% for genotype 2 and 14% for African-Americans with genotype 1
The 5th International Workshop on
Clinical Pharmacology of Hepatitis Therapy
Boston, MA June 23-24, 2010
* Regulatory Requirements for Early Clinical Testing of Novel HCV Antiviral Drugs: FDA Perspective, Jeff Murray, M.D., M.P.H. FDA, Division of Antiviral Products - (06/25/10)
* A European Perspective: EMA and his critical standpoint, Prof. Jean-Michel Pawlotsky, MD, PhD - (06/23/10)
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