Posted on: Wed, 15 Dec 2010 16:10:32 EST
FOSTER CITY, CA, Dec 15, 2010 (MARKETWIRE via COMTEX) --
SciClone Pharmaceuticals, Inc. (NASDAQ: SCLN
PowerRating) today announced topline results from the Company's phase 2b clinical trial of SCV-07 for the treatment of hepatitis C (HCV). The study evaluated the safety and immunomodulatory effects of SCV-07 as a monotherapy and in combination with ribavirin in relapsed HCV patients. Study data demonstrated SCV-07 to be safe and well-tolerated at both administered doses. Topline results showed a clear biological signal from SCV-07 but did not meet the study's primary efficacy endpoint of a 2 log reduction in viral load from baseline level. A secondary measure of efficacy, defined as a reduction in viral load of greater than 0.5 log from baseline level, was seen in 38.5% of the low-dose patients (5/13) and in 44.4% of the high-dose patients (8/18). Additionally, while no patients in the low-dose group achieved greater than a 1 log reduction, 3 of the high-dose patients achieved greater than a 1 log reduction in viral load. This proof of concept study was designed to provide an estimate of SCV-07's treatment effect in relapsed HCV patients and guide further studies of SCV-07 in addressing this chronic infection.
"Although the data showed an interesting biological signal, due to the rapidly changing landscape of effective treatments which increase the complexity and risks of developing drugs in chronic HCV, we have decided not to continue development in this indication. On another front, we continue to be excited about the potential for SCV-07 in the prevention of oral mucositis in patients with head and neck cancer and the initiation of our phase 2b study, which should begin by early 2011," stated Friedhelm Blobel, Ph.D., President and Chief Executive Officer of SciClone. "Our primary focus remains on rapidly growing our commercially successful specialty pharmaceutical business in China and other key emerging markets to increase profitability and generate cash for our shareholders."
Study Design The phase 2b multicenter, multi-dose, open-label study was designed to evaluate the safety and immunomodulatory effects of SCV-07 as a monotherapy or in combination with ribavirin in non-cirrhotic patients with genotype 1 chronic HCV who have relapsed after at least 44 weeks of treatment with pegylated interferon and ribavirin. The study, which also monitored biomarkers of immune activation and HCV viral load dynamics, included two treatment cohorts of 20 patients each who received SCV-07 at a dose of either 0.1 mg/kg or 1.0 mg/kg. The eight week treatment period included four weeks of SCV-07 monotherapy followed by four weeks of SCV-07 in combination with ribavirin. The trial also included three follow-up visits within seven weeks after the completion of treatment.
About SCV-07 SCV-07 (gamma-D-glutamyl-L-tryptophan) is a small molecule which appears to stimulate the immune system through inhibition of STAT3 signaling and the resulting effects on T-helper 1 cells. SCV-07 has been shown to be efficacious in animal models of immune-sensitive diseases, including prevention of oral mucositis, treatment of cancer, viral infections, and enhancement of response to vaccines.
Additionally, SciClone is currently planning to initiate a phase 2b study of SCV-07 for the prevention of oral mucositis by early 2011. As compared to the company's recently completed phase 2a trial, the phase 2b study design is expected to include higher doses of SCV-07 and be adequately powered to demonstrate statistical significance. Additionally, researchers expect to continue to investigate the role of specific genetic profiles on patient response to SCV-07, as well as the potential link between cytokine activity and SCV-07's sub-cellular mechanism of action.
SCV-07 is protected by composition of matter patents as well as multiple method of treatment patents. SciClone has exclusive worldwide rights to SCV-07 outside of Russia, where the molecule has recently been approved for stimulation of depressed immune systems.
About SciClone SciClone Pharmaceuticals (NASDAQ: SCLN) is a revenue-generating, China-centric, specialty pharmaceutical company with a substantial international business and a product portfolio of novel therapies for cancer and infectious diseases. The Company is focused on continuing sales growth and executing a clinical development strategy with prudently managed costs. ZADAXIN(R) (thymalfasin) is approved in over 30 countries for the treatment of hepatitis B (HBV) and hepatitis C (HCV), certain cancers, and as a vaccine adjuvant. In addition to further studying thymalfasin's use as a vaccine enhancer, SciClone is planning to evaluate SCV-07 in a phase 2b trial to modify the course of oral mucositis in patients with head and neck cancer; and recently completed a phase 2b trial of SCV-07 for the treatment of HCV. The Company also has exclusive commercialization and distribution rights in China to a novel treatment for advanced liver cancer, DC Bead(R), currently under review by regulatory agencies in that country. Additionally, SciClone owns exclusive commercialization and distribution rights to the anti-nausea drug ondansetron RapidFilm(R) in China, including Hong Kong and Macau, and Vietnam. The Company intends to seek regulatory approval for the product, commonly used to treat and prevent nausea and vomiting caused by chemotherapy, radiotherapy, and surgery, in these markets. For additional information, please visit www.sciclone.com.
Forward-looking statements The information in this press release contains forward-looking statements, including our expectations and beliefs regarding the timing and results of our clinical trials. You are urged to consider statements that include the words "may," "will," "would," "could," "should," "might," "believes," "estimates," "projects," "potential," "expects," "plans," "anticipates," "intends," "continues," "forecast," "designed," "goal," or the negative of those words or other comparable words to be uncertain and forward-looking. These statements are subject to risks and uncertainties that are difficult to predict and actual outcomes may differ materially. These risks and uncertainties include our forward-looking statements regarding our commercial and development objectives because of uncertainties, including future sales, product pricing, the timing of clinical trial events such as patient enrollment, requirements of, and future actions of, the U.S. Food and Drug Administration, the fact that experimental data, and clinical results derived from studies with animals or a limited group of patients, as well as comparisons with other clinical trials, may not be predictive of the results of larger studies and, therefore, such experimental or clinical data are not necessarily predictive indicative of the efficacy or safety or the results of larger studies and clinical trials. Please also refer to the other risks and uncertainties described in SciClone's filings with the Securities and Exchange Commission. All forward-looking statements are based on information currently available to SciClone, and SciClone assumes no obligation to update any such forward-looking statements.
DC Bead is a registered trademark of Biocompatibles UK Limited.
RapidFilm is a registered trademark of Labtec Gesellschaft fuer technologische Forschung und Entwicklung mbH.
SOURCE: SciClone Pharmaceuticals, Inc.
Source
December 15, 2010
Ontarians deserve better access to treatment for hepatitis B and C
December 15, 2010
ICES study calls for more prevention, more screening and more research but what about treatment?
Toronto, December 15, 2010: Hepatitis B and C are insidious diseases that have few symptoms until they reach an advanced and potentially fatal stage. The time it takes for these diseases to cause cirrhosis or liver cancer may be anywhere from two to 20 years -- more than enough time to intervene. Simple blood tests can identify the hepatitis B and C viruses and yet these tests are not a standard part of annual physicals. Effective treatments also exist for both chronic hepatitis B and C but they are not always accessible to those who need them. With the recent Institute of Clinical Evaluative Sciences (ICES) study ranking hepatitis B and C in the top five most burdensome infectious diseases, the Canadian Liver Foundation is calling upon the provincial government to establish standardized screening protocols and to make treatment more widely accessible for all Ontarians with hepatitis B and C.
“The ICES study should be an eye-opener for everyone,” says Dr. Morris Sherman, Chairman of the Canadian Liver Foundation and a hepatologist at Toronto General Hospital. “It shows that hepatitis B and C are major contributors to morbidity and mortality in Ontario. These diseases have not been a priority for our government despite the major toll they take on our population. The tragedy is that the power to reduce this human cost is within the grasp of government but they have yet to recognize it.”
The study calls for greater screening and preventative measures like immunization (in the case of hepatitis B) to tackle the problem. It is estimated that as many as one third of Ontarians with viral hepatitis do not realize that they have it. If all physicians incorporated hepatitis testing into standard physicals, more patients would be identified and those that had not been exposed to hepatitis B could be immunized. These measures would increase the early identification and intervention but are only part of the solution. Once identified, patients need to have access to affordable treatments in order to prevent the more serious consequences of their disease.
Hepatitis B is the leading cause of liver cancer – a form of cancer that is on the rise in Ontario. If diagnosed at an early stage however, hepatitis B and even liver cancer can be treated effectively. “There are excellent treatments available for hepatitis B that will prevent most of the potentially fatal complications of this disease,” says Dr. Sherman. “And yet, restrictions on funding for treatment exist in most provinces and in Ontario, those restrictions are so tight that most patients who need treatment cannot get reimbursement through the government. With a high proportion of hepatitis B patients coming from the Chinese immigrant community, these policies are particularly discriminatory. Without access to affordable and effective treatments, hepatitis B will continue to contribute to mortality in this province.”
The Canadian Liver Foundation agrees with the report’s recommendation for more funding for research. Hepatitis C is a good example of how investment in research can pay off in a short amount of time. From the virus first being identified in the 1980s, hepatitis C has seen dramatic steps forward in treatment with more on the way. “Improved treatment for hepatitis C is just a few years away,” says Dr. Sherman. “With these new treatments the cure rate will go up from about 45% to 75%. These breakthroughs will give us tremendous opportunity to reduce the burden of this disease but only if the treatments are available to patients regardless of their financial resources.”
“The ICES study sheds light on serious health issues that the Canadian Liver Foundation and the hepatology community have been aware of for some time,” says Dr. Sherman. “While we hope that this report will help open a dialogue on the financial and human costs of hepatitis B and C in this province, we call upon the government to act now to make appropriate treatment for hepatitis B and hepatitis C available to all those who need it to mitigate the effects of these diseases. If this study is repeated in the future, we do not want to see hepatitis B and hepatitis C in the top 10.”
For more information, contact
Melanie Kearns
416-491-3353 ext. 4923
mkearns@liver.ca
Source
ICES study calls for more prevention, more screening and more research but what about treatment?
Toronto, December 15, 2010: Hepatitis B and C are insidious diseases that have few symptoms until they reach an advanced and potentially fatal stage. The time it takes for these diseases to cause cirrhosis or liver cancer may be anywhere from two to 20 years -- more than enough time to intervene. Simple blood tests can identify the hepatitis B and C viruses and yet these tests are not a standard part of annual physicals. Effective treatments also exist for both chronic hepatitis B and C but they are not always accessible to those who need them. With the recent Institute of Clinical Evaluative Sciences (ICES) study ranking hepatitis B and C in the top five most burdensome infectious diseases, the Canadian Liver Foundation is calling upon the provincial government to establish standardized screening protocols and to make treatment more widely accessible for all Ontarians with hepatitis B and C.
“The ICES study should be an eye-opener for everyone,” says Dr. Morris Sherman, Chairman of the Canadian Liver Foundation and a hepatologist at Toronto General Hospital. “It shows that hepatitis B and C are major contributors to morbidity and mortality in Ontario. These diseases have not been a priority for our government despite the major toll they take on our population. The tragedy is that the power to reduce this human cost is within the grasp of government but they have yet to recognize it.”
The study calls for greater screening and preventative measures like immunization (in the case of hepatitis B) to tackle the problem. It is estimated that as many as one third of Ontarians with viral hepatitis do not realize that they have it. If all physicians incorporated hepatitis testing into standard physicals, more patients would be identified and those that had not been exposed to hepatitis B could be immunized. These measures would increase the early identification and intervention but are only part of the solution. Once identified, patients need to have access to affordable treatments in order to prevent the more serious consequences of their disease.
Hepatitis B is the leading cause of liver cancer – a form of cancer that is on the rise in Ontario. If diagnosed at an early stage however, hepatitis B and even liver cancer can be treated effectively. “There are excellent treatments available for hepatitis B that will prevent most of the potentially fatal complications of this disease,” says Dr. Sherman. “And yet, restrictions on funding for treatment exist in most provinces and in Ontario, those restrictions are so tight that most patients who need treatment cannot get reimbursement through the government. With a high proportion of hepatitis B patients coming from the Chinese immigrant community, these policies are particularly discriminatory. Without access to affordable and effective treatments, hepatitis B will continue to contribute to mortality in this province.”
The Canadian Liver Foundation agrees with the report’s recommendation for more funding for research. Hepatitis C is a good example of how investment in research can pay off in a short amount of time. From the virus first being identified in the 1980s, hepatitis C has seen dramatic steps forward in treatment with more on the way. “Improved treatment for hepatitis C is just a few years away,” says Dr. Sherman. “With these new treatments the cure rate will go up from about 45% to 75%. These breakthroughs will give us tremendous opportunity to reduce the burden of this disease but only if the treatments are available to patients regardless of their financial resources.”
“The ICES study sheds light on serious health issues that the Canadian Liver Foundation and the hepatology community have been aware of for some time,” says Dr. Sherman. “While we hope that this report will help open a dialogue on the financial and human costs of hepatitis B and C in this province, we call upon the government to act now to make appropriate treatment for hepatitis B and hepatitis C available to all those who need it to mitigate the effects of these diseases. If this study is repeated in the future, we do not want to see hepatitis B and hepatitis C in the top 10.”
For more information, contact
Melanie Kearns
416-491-3353 ext. 4923
mkearns@liver.ca
Source
How Long Does HCV Live on Surfaces?
Alan Franciscus, Editor-in-Chief
HCV Advocate
How long is HCV stable on exposed (environmental) surfaces? In real world situations it would be almost impossible to effectively study this problem because of the many variables involved in testing blood on exposed surfaces, such as room temperature, amount of blood exposed, viral load (low/high) and various contaminants in the environment. However, a study conducted by the Centers for Disease Control may shed some light on this issue and help provide a better understanding of the infectivity of HCV on surfaces, which will help fine tune HCV prevention measures.
A study conducted by Kris Krawczynski et. al from the Centers for Disease Control and Prevention tested the stability of dried and stored serum (blood) of HCV infected blood in chimpanzees to determine how long HCV infected blood lives on an outside surface as well as the level of infectivity of the blood exposed.
Chimpanzee plasma (CID) divided into 105 infectious doses (genotype 1a) was dried in tubes under vacuum. After overnight drying (~16 hours) samples were either rehydrated with sterile water and stored at -70C or transferred to a controlled environmental chamber (42% humidity, over saturated salt solution) for a 4 or 7 day storage at 25C and subsequently rehydrated with sterile water and kept at -70C.
Samples dried/stored 7 days and dried overnight were used for testing. To determine infectivity, samples of dried/stored plasma for 7 days, 4 days and overnight, were reconstituted in sterile water and injected into a chimpanzee. The size of the infectious dose of each inoculum was calculated at 3.3 x 104 CID. Plasma samples were tested for HCV RNA (viral load), HCV anti-body and alanine aminotransferase (ALT) levels twice weekly. In addition, liver specimens were obtained weekly or biweekly and tested for hepatitis C virus antigen (HCVAg) and histopathology (liver health).
The chimpanzee was first inoculated with the HCV inoculum that was dried and stored for 7 days and followed during 129 days. Subsequently, the chimpanzee was inoculated with the HCV inoculum that was dried and stored for 4 days and followed for 134 days, and finally inoculated with the dried sample overnight and followed for 201 days. Data from three chimpanzees with untreated HCV inoculum were included in the study as a control group.
The authors found that HCV RNA (viral load) was detectable in plasma dried overnight and 7 days, but a ten fold decrease of detectable HCV RNA (viral load) was found in both of the samples compared with the HCV RNA level of the original, untreated HCV positive plasma sample. No evidence of HCV infections was detected in the chimpanzee given either the 7-day or 4-day dried and stored samples. All blood samples tested were negative for HCV RNA and HCV antibodies. In addition, ALT levels remained in the normal range. However after inoculation with the overnight dried sample, HCV RNA was detected in the blood of the chimpanzee from day 7 post inoculation and viral load reached 6.0 to 7.3 logs IU/mL. HCV Ag positive hepatocytes (liver cells) were observed from day 11 post inoculation, seroconversion to anti-HCV was observed on day 127, and the chimpanzee was still positive for HCV RNA (4.8 logs IU/mL) at day 201 post infection. ALT activity level was elevated over the normal range from day 11 post inoculation and remained elevated until the end of the observation period. Virologic, serologic, and clinical evidence of HCV infection and acute hepatitis was found in all three control animals.
The Bottom Line
The authors of this study concluded that infectivity studies in a chimpanzee suggest that HCV may survive on environmental surfaces at room temperature for at least 16 hours but not longer than 4 days. The potential for HCV to survive in the environment re-emphasizes the importance of cleaning and disinfection procedures, safe therapeutic injection practices, and harm reduction counseling and services for injection drug users.
Source
Also See:
HCV Outside the Body: How Well Does It Survive on Surfaces, in Syringes, and in the Lab?
HCV Advocate
How long is HCV stable on exposed (environmental) surfaces? In real world situations it would be almost impossible to effectively study this problem because of the many variables involved in testing blood on exposed surfaces, such as room temperature, amount of blood exposed, viral load (low/high) and various contaminants in the environment. However, a study conducted by the Centers for Disease Control may shed some light on this issue and help provide a better understanding of the infectivity of HCV on surfaces, which will help fine tune HCV prevention measures.
A study conducted by Kris Krawczynski et. al from the Centers for Disease Control and Prevention tested the stability of dried and stored serum (blood) of HCV infected blood in chimpanzees to determine how long HCV infected blood lives on an outside surface as well as the level of infectivity of the blood exposed.
Chimpanzee plasma (CID) divided into 105 infectious doses (genotype 1a) was dried in tubes under vacuum. After overnight drying (~16 hours) samples were either rehydrated with sterile water and stored at -70C or transferred to a controlled environmental chamber (42% humidity, over saturated salt solution) for a 4 or 7 day storage at 25C and subsequently rehydrated with sterile water and kept at -70C.
Samples dried/stored 7 days and dried overnight were used for testing. To determine infectivity, samples of dried/stored plasma for 7 days, 4 days and overnight, were reconstituted in sterile water and injected into a chimpanzee. The size of the infectious dose of each inoculum was calculated at 3.3 x 104 CID. Plasma samples were tested for HCV RNA (viral load), HCV anti-body and alanine aminotransferase (ALT) levels twice weekly. In addition, liver specimens were obtained weekly or biweekly and tested for hepatitis C virus antigen (HCVAg) and histopathology (liver health).
The chimpanzee was first inoculated with the HCV inoculum that was dried and stored for 7 days and followed during 129 days. Subsequently, the chimpanzee was inoculated with the HCV inoculum that was dried and stored for 4 days and followed for 134 days, and finally inoculated with the dried sample overnight and followed for 201 days. Data from three chimpanzees with untreated HCV inoculum were included in the study as a control group.
The authors found that HCV RNA (viral load) was detectable in plasma dried overnight and 7 days, but a ten fold decrease of detectable HCV RNA (viral load) was found in both of the samples compared with the HCV RNA level of the original, untreated HCV positive plasma sample. No evidence of HCV infections was detected in the chimpanzee given either the 7-day or 4-day dried and stored samples. All blood samples tested were negative for HCV RNA and HCV antibodies. In addition, ALT levels remained in the normal range. However after inoculation with the overnight dried sample, HCV RNA was detected in the blood of the chimpanzee from day 7 post inoculation and viral load reached 6.0 to 7.3 logs IU/mL. HCV Ag positive hepatocytes (liver cells) were observed from day 11 post inoculation, seroconversion to anti-HCV was observed on day 127, and the chimpanzee was still positive for HCV RNA (4.8 logs IU/mL) at day 201 post infection. ALT activity level was elevated over the normal range from day 11 post inoculation and remained elevated until the end of the observation period. Virologic, serologic, and clinical evidence of HCV infection and acute hepatitis was found in all three control animals.
The Bottom Line
The authors of this study concluded that infectivity studies in a chimpanzee suggest that HCV may survive on environmental surfaces at room temperature for at least 16 hours but not longer than 4 days. The potential for HCV to survive in the environment re-emphasizes the importance of cleaning and disinfection procedures, safe therapeutic injection practices, and harm reduction counseling and services for injection drug users.
Source
Also See:
HCV Outside the Body: How Well Does It Survive on Surfaces, in Syringes, and in the Lab?
IL28B and the Control of Hepatitis C Virus Infection
Gastroenterology
Volume 139, Issue 6 , Pages 1865-1876, December 2010
Ashwin Balagopal, David L. Thomas, Chloe L. Thio
Received 6 August 2010; accepted 8 October 2010. published online 14 October 2010.
John P. Lynch and David C. Metz, Section Editors
Treatment-induced control and spontaneous clearance of hepatitis C virus (HCV) infection are affected by various host factors. Polymorphisms in the region of the gene IL28B are associated with HCV clearance, implicating the gene product, interferon (IFN)-λ3, in the immune response to HCV. Although it is not clear how the IL28B haplotype affects HCV clearance, IFN-λ3 up-regulates interferon-stimulated genes, similar to IFN-α and IFN-β but via a different receptor. There is also evidence that IFN-λ3 affects the adaptive immune response. The IL28B genotype can be considered, along with other factors, in predicting patient responses to therapy with pegylated IFN-α and ribavirin. We review the genetic studies that uncovered the association between IL28B and HCV clearance, the biology of IFN-λ3, the clinical implications of the genetic association, and areas of future research.
Keywords: IL28B, Hepatitis C Virus, Interferon Lambda, Interferon Sensitivity, HCV Treatment
Abbreviations used in this paper: GWAS, genome-wide association studies, HIV, human immunodeficiency virus, IFN, interferon, IL-10Rβ, interleukin-10 receptor beta chain, IL-28Rα, interleukin-28 receptor alpha chain, ISG, interferon-stimulated gene, PEG, pegylated, RBV, ribavirin, SNP, single nucleotide polymorphism, STAT, signal transducers and activators of transcription, SVR, sustained virologic response
Spontaneous clearance of hepatitis C virus (HCV) occurs in ∼30% of patients with acute infections; the remaining patients develop chronic infections and have predispositions to cirrhosis and hepatocellular carcinoma.1, 2, 3 Among chronically infected patients, HCV can be cleared by interferon (IFN)-α–based treatment in some cases. Researchers have searched for factors responsible for natural and treatment-induced HCV clearance for more than 10 years. In the past year, genetic studies have identified several single nucleotide polymorphisms (SNPs) in and near IL28B (which encodes IFN-λ3) that are associated with clearance. We review the role of IL28B in HCV infection, clinical implications, and directions for future research.
Overview of the IFN-λ Family
IFN-λ3 belongs to the IFN-λ family, along with IFN-λ1 and IFN-λ2, which are encoded by IL29 and IL28A, respectively. IFN-λs are categorized as type 3 IFNs and are potent, endogenous antiviral cytokines. Although they are structurally most homologous to members of the IL10 family, IFN-λs are more functionally similar to type 1 IFNs4; they signal via Jak/signal transducers and activators of transcription (STAT) intracellular pathways and up-regulate transcription of IFN-stimulated genes (ISGs) that are required to control viral infection. IFN-λ–like sequences have been found in most mammalian species, but many are pseudogenes.5 Phylogenetic studies of type 1 and type 3 IFNs and the interleukin-10 family of cytokines indicate the existence of a common, ancestral IFN gene that shared the multi-exon genomic structure of the IFN-λ family members; it was putatively identified in ancient fish, evolved in a series of gene duplication and retrotransposon events, and gave rise to the IFNs observed in mammals.5 In humans, the IFN-λ genes cluster on chromosome 19 (Figure 1).5
IFN-λs inhibit HCV replication in vitro,6, 7, 8 and trials of IFN-λ1 in patients with chronic HCV infections have shown promising results9; 86% of treatment naive-patients who received combined pegylated (PEG) IFN-λ and ribavirin (RBV) for 4 weeks had a >2 log10 IU/mL decrease in HCV RNA. Therefore, associations made between IL28B variants and HCV clearance in large-scale genetic studies provide an exciting mechanistic link between innate immunity and viral clearance.
IL28B and Control of HCV Infection With Therapy
Many of the first studies that linked IL28B and HCV clearance came from studies of large cohorts of patients with chronic HCV infection who were treated with PEG-IFN-α and RBV. These cohorts were investigated in genome-wide association studies (GWAS), which allow an unbiased sampling of variations in genes across the entire genome without a hypothesis. The first GWAS was performed using an Illumina Human610Quad BeadChip (San Diego, CA) in the IDEAL study, in which patients infected with HCV genotype 1 were randomly assigned to groups that were treated with PEG-IFN-α2a or PEG-IFN-α2b; the study included only subjects who were treated with a minimum number of total doses.10 Although more than 500,000 SNPs were considered, the investigators found that the strongest predictor of sustained virologic response (SVR) was a SNP (rs12979860) located on the long arm of chromosome 19, within the IFN-λ gene cluster (Figure 2). IL28B is upstream and in the reverse orientation of IL28A; rs12979860 is upstream of both of these genes, closer to IL28B (Figure 1). At this position, the C allele is the most frequently observed in the white population (but not in the black population) and is associated with SVR; people with the CC genotype have SVR rates more than 2-fold higher than those with the minor T allele (Table 1). In addition to this SNP, the 6 SNPs most strongly associated with SVR were also found at the IFN-λ gene cluster, although the effects of these were no longer observed after adjusting for the presence of rs12979860. After adjusting for the association of rs12979860, the next SNP most strongly associated with SVR found in the GWAS was rs8099917, a noncoding SNP found ∼7.5 kilobases upstream of the IL28B start codon. These findings were validated in a study that genotyped the rs12979860 SNP in patients from the Duke Hepatology Clinical Research Database and Respository, a registry of patients with HCV infections who were followed up longitudinally.11 The subjects had HCV genotype 1 (80.5%) or genotype 2 or 3 (19.5%) infections and had received complete courses of PEG-IFN-α and RBV therapy. White subjects, who made up most of the study group, with the CC genotype were >5 times more likely to achieve an SVR than subjects with the CT or TT genotypes (P = 9.0 × 10−6). Differences in treatment outcomes among black subjects were not significantly associated with the IL28B genotype, although the investigators acknowledged the limited power of the study given the smaller numbers of black subjects included (n = 106). The association of IL28B genotype with SVR was independent of treatment history. In contrast to treatment response, relapse was not associated with IL28B genotype.
Three other groups used similar approaches to study the genetic basis for SVR and found a group of SNPs near IL28B that were in strong linkage disequilibrium, indicating that they were inherited as a block rather than independently. Depending on the technology used and the racial composition of the study population, the specific findings of each study varied (detailed in the following text; Figure 1 and Table 1). Collectively, the results showed that there is a genomic region comprising IL28B and its potential regulatory sequences that is strongly associated with IFN response (Figure 3). Suppiah et al studied Australians of European descent with HCV genotype 1 infections who received PEG-IFN-α and RBV.12 In the first phase, a GWAS was performed on all participants and results were compared between patients who achieved an SVR while receiving treatment and those who did not respond. Several SNPs were associated with clearance, but the strongest was rs8099917. Compared with the T allele, heterozygosity for the minor G allele was associated with a 1.64-fold increase in risk for not responding to therapy and homozygosity was associated with a 2.39-fold increase in risk.
Tanaka et al performed a GWAS using an Affymetrix SNP Array (Santa Clara, CA) of DNA from HCV genotype 1–infected Japanese patients who achieved an SVR to therapy with PEG-IFN-α2a or PEG-IFN-α2b and RBV, comparing data with that of nonresponders.13 The SNPs rs8099917 and rs12980275 segregated with treatment response (Figure 1). Rauch et al performed a GWAS of the Swiss Hepatitis C Cohort, a population of European white subjects infected with HCV genotypes 1 (48%), 2 (10%), 3 (29%), and 4 (9%) who received PEG-IFN-α and RBV.14 The most significant markers were clustered at the IFN-λ gene loci. The SNP rs8099917 was most highly associated with response to treatment, also reported by Suppiah et al and Tanaka et al (Figure 1). Only 73.9% of patients homozygous for the T allele achieved an SVR, but patients with the minor G allele were 5-fold less likely to respond to therapy (P = 3.11 × 10−8). It is important to note that these investigators used different GWAS platforms than Ge et al10 (Figure 1). The rs12979860 was associated with SVR in subsequent studies, but this association was not fully tested; Tanaka et al did not include rs12979860 in their GWAS platform, and Suppiah et al and Rauch et al used multiple platforms with only limited representation of this SNP. Rauch et al did report that where data were available for rs12979860 it was linked to rs8099917.
IL28B Mapping and HCV Control
It appears that an IL28B haplotype can be a strong determinant of a patient's response to treatment of HCV infection and can be represented by a single SNP (or a small number of SNPs) (Figure 3). Several groups performed more finely tuned genetic studies to clarify which SNP(s) had the greatest associations with treatment response. Ge et al sequenced the IL28B gene in a subset of patients to find genetic markers that were in high linkage disequilibrium with the SNP rs12979860, identified in their GWAS.10 Two additional markers were found: a nonsynonymous SNP (rs8103142) within the IL28B gene that encodes a lysine → arginine substitution at position 70 (K70R) and a G → C substitution (rs28416813) 37 base pairs upstream of the translation initiation site (Figure 1). These 3 SNPs were tightly linked, so it was a challenge to associate any one, individually, with treatment response. Suppiah et al genotyped 20 additional SNPs within the IL28B gene in an expanded cohort that included white subjects from Europe and Australia and compared frequencies between subjects who did and did not achieve an SVR.12 A G allele at rs12980275 had the strongest association with nonresponse (Figure 2). In this study, a 6-allele haplotype was identified that also included K70R (T > C on the coding strand); the haplotype with an arginine (R) was associated with nonresponse.
Similarly, Tanaka et al sequenced 16 SNPs in a validation cohort, based on HapMap data that characterized chromosome 19.13 Although they associated the haplotype, which included K70R, with response to therapy, it did not have a significantly greater association with SVR than any of the individual SNPs; thus, any single SNP is sufficient to mark the association with an SVR. In a logistic regression model, rs8099917 was most predictive of an SVR. Rauch et al sequenced the IL28B gene in subjects with the TT genotype at rs8099917 (associated with response) who achieved the expected SVR and those who did not achieve an SVR (the unexpected outcome).14 They also sequenced DNA from subjects with the risk GG genotype with the expected outcome of nonresponse to therapy and from those who achieved an SVR despite carrying this genotype. Twenty-one additional SNPs were identified that fell into 1 of 2 haplotype families. The first family was associated with HCV clearance, and the second was associated with persistence. As with Suppiah et al, an R at amino acid position 70 was found in the risk haplotype, along with another SNP (rs28416813) identified by Ge et al.10, 12, 14 These genetic mapping studies identified the specific alleles associated with response (or lack of response) to anti-HCV therapy (Figure 3).
IL28B and Spontaneous Clearance
The same IL28B haplotypes associated with treatment response are also associated with spontaneous clearance of HCV. Thomas et al genotyped the rs12979860 SNP in more than 1000 people from 6 cohorts with well-characterized spontaneous clearance of HCV or viral persistence and found that the CC genotype was strongly associated with HCV clearance (odds ratio, 0.33; P < 10−12).15 The investigators also showed that the clearance was mediated by linkage of this genotype with other identified markers, because their inclusion in a multivariate model did not reduce the association between the CC genotype and viral clearance. Ge et al had observed the clearance effect of the C allele at a higher frequency (73%) in a population with unknown HCV status compared with patients with chronic infections who went on to receive treatment (63%; P = 2.48 × 10−6), suggesting that this allele occurred more frequently among patients with spontaneous clearance of HCV.10 Further evidence that IL28B is involved in spontaneous clearance was provided by Rauch et al using a GWAS.14 They associated the T allele of rs8099917 with spontaneous clearance; no SNPs outside the IL28B/A gene loci were associated with clearance. In studies of a cohort of Spanish patients with acute HCV infection and a cohort of German patients with acute HCV infections (from the anti-D common source outbreak), researchers reported that the CC genotype at rs12979860 was observed more frequently in subjects with spontaneous resolution of HCV.16, 17 These results indicate the involvement of the same IL28B SNPs in both spontaneous and treatment-induced control of HCV infection (Figure 3).
IL28B and Racial Differences in HCV Control
Because SNPs in IL28B have varied distributions among ethnic groups (Table 2; http://www.hapmap.org/), it is intriguing to consider whether the differences at this locus account for the association between white ethnicity and increased spontaneous and treatment-induced clearances. Of the 2 alleles most strongly associated with HCV clearance (rs12979860 C and rs8099917 T), only the former is more common in people of European compared with African descent (Table 2 and Figure 4; hapmap.org); it might underlie the racial differences observed. Thomas et al genotyped the rs12979860 SNP in more than 2000 people from 51 ethnic populations worldwide and showed that East Asian populations have the highest frequencies of the alleles associated with clearance, sub-Saharan African populations have the lowest frequencies, and European populations have intermediate frequencies (Figure 4).15 In their study population, Ge et al also found the lowest frequencies of the allele associated with clearance among black subjects (allele frequency, ∼0.42), the highest frequencies in East Asian subjects (∼0.95), and intermediate frequencies in European-American (∼0.73) and Hispanic (∼0.7) subjects; these findings were validated in a subsequent study.10, 11 This distribution of alleles could account for the high rates of treatment-induced SVR observed in East Asian subjects.18, 19 When this SNP was studied in multivariate models of spontaneous and treatment-induced clearance, however, it accounted for only ∼50% to 60% of the ethnic differences observed in HCV control (D. L. Thomas, personal communication, August, 2010).10 It is notable that only 53% of black subjects with this genotype achieved an SVR compared with 82% of white subjects. Other genetic factors beyond IL28B genotype mediate spontaneous and treatment-associated clearance of HCV, although within a given race, IL28B genotype does predict outcome.
IL28B in HCV Genotype 2 and 3 Infections
Most of the initial studies of IL28B and HCV control were centered on people with HCV genotype 1 infections; studies of IL28B in patients infected with HCV of other genotypes have produced conflicting data and included small numbers. The largest study included 268 subjects infected with HCV genotype 2/3 who were randomly assigned to groups that were given PEG-IFN-α and RBV for a standard (24 weeks) or variable duration (12 weeks if they had a rapid virologic response or 24 weeks if they did not).20 Surprisingly, the genotype of IL28B was not associated with SVR in subjects who received standard duration therapy or who achieved a rapid virologic response and received variable therapy (12 weeks). There was a strong association between IL28B and treatment response only among subjects who did not achieve a rapid virologic response and received variable therapy (24 weeks). Intriguingly, in this subset, there appeared to be an effect of gene dose; IL28B heterozygotes had an intermediate rate of SVR, between that of patients with homozygosity for alleles that were and were not associated with clearance.
Several other studies have produced mixed results. Montes-Cano et al associated the IL28B haplotype with an SVR in a cohort of Spanish patients with non–genotype 1 infections.16 McCarthy et al found that the effect of the IL28B haplotype on SVR was similar between subjects with HCV genotypes 1 and 2/3.11 The inclusion of IL28B genotype in a multivariate model, however, reduced only slightly the influence of HCV genotype on SVR. In contrast, Rauch et al noted a trend in the effect of the IL28B haplotype in subjects infected with HCV genotypes 2/3, but this was not statistically significant,14 whereas Rallon et al did not associate the IL28B haplotype with treatment response in people infected with HCV genotype 3.21 The effect of the IL28B haplotype status on treatment response might therefore be attenuated for genotypes 2 and 3, but further research is required to clarify this relationship.
IL28B in Patients Coinfected With Human Immunodeficiency Virus and HCV
About one third of people infected with human immunodeficiency virus (HIV) are also infected with HCV. HIV complicates HCV infection by increasing rates of HCV persistence.2 Despite the immunologic changes associated with HIV infection, it does not affect the association between SNPs near the IFN-λ gene cluster and clearance of HCV. Thomas et al reported that stratification based on HIV status did not modulate the effect of the SNP rs12979860 on HCV clearance.15 Similarly, in a subset of patients in the Swiss Hepatitis C Cohort who were infected with HIV, Rauch et al found that the SNP rs8099917 was still associated with HCV clearance; effects of this SNP did not differ markedly between HCV-infected patients with or without HIV infection.14 Rallon et al found that among patients coinfected with HIV and HCV who completed PEG-IFN-α and RBV treatment, the CC genotype at locus rs12979860 was associated with an SVR and the association was strongest among patients infected with HCV genotypes 1 or 4.21 Given the low rates of spontaneous clearance and treatment-induced SVR among people coinfected with HIV and HCV, it is striking that IL28B is still associated with HCV control in this population.
IL28B and Other Infectious Diseases
Martin et al investigated whether IL28B SNPs are important in the control of other chronic viral infections where IFN-α is important in the immune response.22 A cohort of 226 individuals with persistent hepatitis B virus (HBV) infection was compared with 384 individuals who had recovered from HBV infection; recovery was not associated with the rs12979860 SNP. They also studied a cohort of 2548 individuals with, or who were at high risk for, HIV infection and found that the rs12979860 SNP was not associated with infection with HIV or disease progression. In GWAS with the Illumina HumanHap550 BeadChip, Kamatani et al studied patients with chronic HBV infection and found no association of chronic infection with IL28B genotype.23 Similarly, Fellay et al studied HIV-infected subjects using the Illumina BeadChip and found no association of IL28B with either HIV-1 viral RNA set point or with disease progression.24 Polymorphisms in IL28B have therefore not been associated with clearance of other viral infections.
The Effect of IL28B on HCV RNA Levels, Viral Kinetics, and IFN Responsiveness
Several groups have studied the correlation of IL28B genotype, baseline levels of HCV RNA, and treatment response. Ge et al found that although the C allele of rs12979860 was associated with SVR, it was also, paradoxically, associated with higher viral RNA levels compared with the T allele (CC patients had 6.35 log10 IU/mL, TC patients had 6.33 log10 IU/mL, and TT patients had 6.16 log10 IU/mL; P = 1.21 × 10−10).10 Higher levels of HCV RNA levels were also observed in patients who were off therapy who had the C allele.11 Although the differences are modest (<0.5 log10), the higher levels of HCV RNA among patients with the CC genotype might facilitate innate immune detection and control of the virus during treatment.
In addition to baseline level of HCV RNA, the kinetics of the treatment response appears to be influenced by IL28B genotype. Thompson et al compared viral kinetic data between subjects with CC, CT, and TT genotypes at the rs12979860 SNP 2 weeks after they began therapy with PEG-IFN-α and RBV.25 Irrespective of race, subjects with the CC genotype had the largest reductions in levels of HCV RNA (white subjects with CC genotype had the greatest decrease in HCV RNA). This translated to greater rapid virologic response and early virologic response rates among subjects with the CC genotype. Much of the effect of the IL28B genotype is evident in the first 48 hours after treatment, indicating that IL28B genotype somehow primes the host response to HCV, decreasing the threshold for virologic control with treatment. Alternatively, IL28B genotype could simply be a marker for greater baseline levels of the IFN response, consistent with the findings in patients with spontaneous clearance of HCV.
Intriguingly, Honda et al found that subjects with the TT genotype at the SNP rs8099917 (associated with SVR) had pretreatment hepatic expression levels of ISGs that were lower than those of subjects with the TG or GG genotypes.26 The fact that subjects with genotypes associated with SVR have reduced expression of ISGs might account for the higher levels of HCV RNA observed before treatment. Sensitivity to exogenous IFN is inversely associated with levels of ISGs; IL28B genotypes may affect expression levels of ISGs, accounting for the association between IL28B genotype and response to therapy.27, 28 Despite the association of IL28B with clearance, there are people who carry alleles that are not associated with clearance who clear the virus, as well as patients with alleles associated with clearance whose infection persists. Further studies should be performed with these patients to investigate IL28B genetics, ISG expression levels, and other genetic factors involved in the response to anti-HCV therapy.
IFN-λ Biology and Role in HCV Infection
IL28B can determine the outcome of HCV infection, but the mechanisms that mediate the association between the different SNPs and HCV control are unclear, especially in light of the lack of association of IL28B polymorphisms with HBV or HIV infection outcomes. Investigating the biology of IFN-λ in HCV and other viral infections could provide mechanistic insight.
The main cellular sources of IFN-λs are believed to be plasmacytoid dendritic cells, although macrophages and conventional dendritic cells probably also produce IFN-λs.29 It is not known which cells produce IFN-λs in the liver, but candidates include Kupffer cells, dendritic cells, and liver sinusoidal endothelial cells. Hepatocytes also have active innate immune responses and probably release IFN-λs on viral infection.6, 7 Although IFN-λs have many effects on a number of viruses, their site of action is constrained by expression of their cognate receptor. IFN-λs signal through a heterodimer that comprises the interleukin-28 receptor α chain (IL-28Rα) and the interleukin-10 receptor β chain (IL-10Rβ). In contrast to the distribution of IFN-α receptor and even IL-10Rβ, which are found on a wide variety of cell types, IL-28Rα is found primarily on epithelial cells. This has implications on which cells IFN-λs can act on; in one study, livers from mice were found to express only low levels of IL-28Rα.30
Downstream signaling after IFN-λ receptor ligation, however, is similar to type 1 IFN signaling and occurs via the covalently bound tyrosine kinases Tyk2 and Jak1 (Figure 5).29 These binding partners phosphorylate each other and also phosphorylate STAT1 and STAT2 proteins. A consequence of phosphorylation of STAT1 and STAT2 is the formation of the IFN-stimulated gene factor 3 complex along with activated IFN-regulatory factor 9, which leads to the up-regulation of canonical ISGs. ISG up-regulation causes many of the innate cellular defenses against viral infection. Overall, IFN-λ signaling is believed to be proinflammatory and unlike responses to IL-10, despite sharing the IL-10 receptor subunit.
In addition to phosphorylation of STAT1 and STAT2, STAT3, STAT4, and STAT5 can also be activated via the IL-10Rβ chain, which can have immunomodulatory effects.29 IFN-λ1 and IFN-λ2 inhibit IL-13 production by T cells following stimulation with concanavalin A, indicating that IFN-λs promote the T-helper cell 1 response.31, 32 IFN-λ3 increases the T-helper cell 1 response to an HIV DNA vaccine and simultaneously inhibits regulatory T-cell responses.33 More investigations into the effect of IFN-λs on adaptive immunity could reveal that HCV control by IFN-λ is the result of a multi-level response.
It is not clear how the SNPs in IL28B affect the IFN signaling pathways. The rs12979860 is 3 kilobases upstream of IL28B, whereas rs8099917 is nearly 8 kilobases upstream (Figure 1). Although it is possible that these SNPs modulate IL28B transcription, it is more likely that they are in linkage disequilibrium with one or more SNPs in the IL28B coding or promoter regions. Alternatively, the SNPs could modify transcription factor binding sites. IL29 has multiple IFN-regulatory factor and nuclear factor κB binding sites (eg, −214 to −172 and −98 to −89 upstream of the transcription initiation site), although those that have been reported are not polymorphic.34 The SNP that encodes K70R is important to study because it is tightly linked with SNPs associated with SVR and natural clearance. K70R is not predicted to affect binding to the receptor or signaling, but it could be involved in interactions with other signaling factors that affect viral control.4 The SNPs in IL28B might lead to expression of forms of IFN-λ3 that do not function or have weak function or even hyperfunctional variants that reduce the antiviral response by negative feedback. Research is required to determine how IL28B and its variants affect HCV persistence and response to therapy.
Because IFN-λs inhibit viral replication, it is logical to consider that expression of different amounts of endogenous IFN-λ3 could determine whether a patient controls the virus or remains infected. Two studies compared messenger RNA levels of IFN-λ in whole blood or peripheral blood mononuclear cells from subjects with the T allele at position rs8099917 (associated with clearance) with that of subjects with the G allele (associated with viral persistence).12, 13 It has been difficult to quantify IFN-λ2 and IFN-λ3 messenger RNA levels by polymerase chain reaction because of their sequence homology; levels of IFN-λ2 and IFN-λ3 measured by quantitative polymerase chain reaction are combined when reported. Each group found the highest expression of IFN-λ2 and IFN-λ3 in subjects with the TT genotype, compared with TG and GG genotypes, associating higher amounts of endogenous IFN-λs with HCV clearance. Using information from the SNPExpress database, Ge et al, in contrast, did not observe differences in IFN-λ3 expression among subjects not infected with HCV who were homozygous for an allele in linkage disequilibrium with the rs12979860 SNP (see supplemental data for Ge et al).10 Similarly, Honda et al found no association between hepatic expression of IFN-λ2 and IFN-λ3 and rs8099917 genotype.26 Studies of plasmacytoid dendritic cells and cells that produce IFN-λ in the liver should provide insight into the relationship between the IL28B genotype and expression.
Studies of animals with viral infections indicate that the organ-specific distribution of IL-28Rα determines response to IFN-λ. While some studies observed that IFN-λ protects mice against respiratory but not hepatic viruses,35, 36 others found protection against hepatic viral infection.37 One study made the surprising observation that IFN-λ did not induce expression of ISGs in livers of mice.30 Studies in mice should be interpreted cautiously, however; in human cells and tissues, IFN-λ expression was shown to affect hepatotropic viruses. Robek et al found that IFN-λ1 and IFN-λ2 inhibited HBV replication.6 Moreover, recombinant IFN-λ3 had a more potent antiviral effect than IFN-λ1 or IFN-λ2 against encephalomyocarditis virus in hepatocyte cell lines.38 There has not been an extensive, published study of whether primary human hepatic cells respond to IFN-λ, although in one report HCV-infected liver tissue had higher amounts of IL-28Rα than uninfected liver tissue.39 Interestingly, treatment of macrophages with IFN-λ1 inhibited HIV-1 infection, possibly through production of competitive ligands for HIV coreceptors; it is not clear how this finding might relate to HCV clearance in patients.40
Several in vitro studies support a direct role for IFN-λ for the control of HCV replication through the innate immune pathway. Robek et al showed that subgenomic and full-length HCV replicons were inhibited by recombinant IFN-λ1 and IFN-λ2, which up-regulated a representative ISG.6 In a cell culture system, Marcello et al7 showed that IFN-λ1 inhibited HCV replication with similar kinetics to that of IFN-α but that IFN-λ1–induced up-regulation of ISGs was stronger and lasted longer. Combinations of IFN-λ1 and IFN-α had the greatest inhibitory effect on HCV replication compared with individual agents.8 IFN-λ and IFN-α might therefore have synergistic effects in controlling HCV infection. Type 1 IFN potentiated IFN-λ release in an animal model of viral infection.41 It is possible that the putative SNPs alter the interaction of IFN-λ with IFN-α.
Clinical Implications
The IL28B genotype provides important, independent information about a patient's likelihood of achieving an SVR, and a commercial test became available in the United States in July 2010. Results from this test could be used in combination with algorithms based on HCV genotype and viral load to predict patients' responses to treatment; IL28B genotype could be a factor that patients and their physicians use to decide whether to initiate therapy or wait until direct antiviral agents become available. Unfortunately, IL28B genotype does not have a positive predictive value of 100% for SVR, so it cannot be used as the only predictor of response (Table 1); HCV treatment should not be withheld based solely on IL28B genotype. In addition, the positive predictive value is influenced by the prevalence of SVR, which is difficult to extrapolate from published studies in which patients with ambiguous outcomes were removed from the analyses and the proportions of patients that achieve SVRs varied. To put some numbers in perspective, the SVR rate for black subjects with the rs12979860 CC genotype (associated with clearance) was 53%10; this is similar to that of white subjects with genotype 1 HCV, irrespective of IL28B genotype. Among white subjects in the same study, the SVR rate for those with the rs12979860 CC genotype was ∼82%. Interestingly, when the likelihood of SVR approaches 80%, IL28B genotype can also affect the decision for liver disease staging before treatment. Just as patients with genotype 2 or 3 HCV infection can elect to undergo treatment without consideration of fibrosis stage, people who have IL28B genotypes associated with viral control might decide not to undergo biopsy evaluation. In either case, noninvasive staging is still recommended to determine whether patients should be screened for hepatocellular carcinoma.42
IL28B genotype can affect how long a clinician should monitor someone with an acute HCV infection before treatment. Those with a haplotype associated with HCV clearance might be monitored longer, because they are more likely to spontaneously clear the virus; those with haplotypes associated with persistence might be better off receiving therapy during the acute period and be monitored for a shorter period beforehand.43 The association between kinetics of HCV response to IFN treatment and IL28B genotype might be used to identify patients who require shorter durations of therapy; further studies are required to determine if this is the case. The association between sensitivity to IFN therapy and IL28B genotype could also affect how clinicians use direct antiviral agents. For example, IFN lead-in dosing might be the best option for patients with IL28B haplotypes that are not associated with HCV clearance; they are more likely to develop resistance to direct antiviral agents because their response to IFN-α therapy is slower.
As therapeutic agents, IFN-λs might have longer and more potent effects than type 1 IFNs, with fewer adverse events, because distribution of IFN-λ receptors is more restricted. Phase 1 trials of IFN-λ1 in treatment-naive patients and those with chronic HCV who experienced a relapse after therapy have shown significant reductions in HCV viremia after 4 weeks.9 It will be interesting to see if polymorphisms in IL28B predict a response to IFN-λs in these trials; later-stage trials are under way.
Future Directions
Basic science studies help us understand how specific genetic features relate to immunologic function and HCV clearance. It is important to determine exactly which SNP or specific genetic feature of IL28B affects clearance, and this could require sequencing of IL28A and IL29 in different ethnic groups of patients with natural and treatment-induced clearance to understand linkage in this region. Comparing the human IL28B sequence with that of chimpanzees and other primates might also provide important information about linkage. Although the same gene cluster and SNPs are associated with clearance versus persistence and an SVR versus no response to therapy, these gene variants might affect responses via different mechanisms. The structure of IFN-λ3 has been determined, but the active-site amino acids have only been inferred from alanine scans; the role of SNPs in the IL28B coding region might be more precisely defined by resolving the structure of IFN-λ3 bound to its heterodimeric receptor. Investigations into the genetics of HCV control are hampered by inadequate model systems of HCV infection; animals with phenotypes that more closely resemble patients with HCV infection would improve our understanding of the role of IFN-λ3 in HCV infection. Several HCV cell culture systems exist and studies are under way to examine the role of IL28B in HCV replication using site-directed mutagenesis to compare major and minor alleles for several SNPs. Similarly, knockout mice with humanized livers can be used to study the effects of IFN-λ3 on the immune response and HCV control. Because IFN-λs can have redundant effects, responses to IFN-λ might need to be fully suppressed by interfering with IL-28Rα signaling. Using combined approaches, ISG responses to HCV can be determined using cell culture systems, animal models, small interfering RNAs, and antibodies that inhibit IFN-λ signaling.
In situ studies of liver tissues from patients with chronic HCV infection are necessary to delineate which cells release or respond to IFN-λs, especially given findings from mouse studies that hepatic expression of IL28Rα is limited. Studies should be performed in human hepatic tissue to compare expression of IFN-λ with its receptor. IL28B genotype is assumed to predict the early stages of HCV control, but other immunologic factors, such as pretreatment levels of ISG, might also predict response. It will be important to determine whether IL28B SNPs also predict response to small molecule therapeutics, their utility in patients with acute HCV infections, and optimal treatment duration. There is evidence that IL28B is associated with an SVR in subjects with chronic HCV who were treated with the protease inhibitor telaprevir in addition to standard therapy.44 The paradox of the association of IL28B genotypes that promote HCV clearance and higher baseline levels of HCV RNA should be further evaluated; usually patients with poor response to treatment have high pretreatment levels of HCV RNA. IL28B genotype might not predict clearance of all HCV genotypes, and the interaction between host and viral genotypes should be further explored. Interest in IL28B genotype has extended to other chronic viral infections, and researchers are investigating whether genotypes associated with HCV clearance have other effects in the immune response to pathogens. The identification of IL28B heralds the era of genomic medicine in HCV and opens the door to understanding HCV clearance. The finding has spurred intense bidirectional investigation into the clinic and the bench with the hopes of enhanced therapies against HCV. The coming months and years promise rapid fulfillment of some of these goals and healthy excitement in the field.
References
1.Wilson LE, Torbenson M, Astemborski J, et al. Progression of liver fibrosis among injection drug users with chronic hepatitis C. Hepatology. 2006;43:788–795
2.Thomas DL, Astemborski J, Rai RM, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA. 2000;284:450–456
3.Thomas DL, Seeff LB. Natural history of hepatitis C. Clin Liver Dis. 2005;9:383–398vi
4.Gad HH, Dellgren C, Hamming OJ, et al. Interferon-lambda is functionally an interferon but structurally related to the interleukin-10 family. J Biol Chem. 2009;284:20869–20875
5.Fox BA, Sheppard PO, O'Hara PJ. The role of genomic data in the discovery, annotation and evolutionary interpretation of the interferon-lambda family. PLoS One. 2009;4:e4933
6.Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication. J Virol. 2005;79:3851–3854
7.Marcello T, Grakoui A, Barba-Spaeth G, et al. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology. 2006;131:1887–1898
8.Pagliaccetti NE, Eduardo R, Kleinstein SH, et al. Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication. J Biol Chem. 2008;283:30079–30089
9.Muir AJ, Shiffman ML, Zaman A, et al. Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection. Hepatology. 2010;52:822–832
10.Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401
11.McCarthy JJ, Li JH, Thompson A, et al. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology. 2010;138:2307–2314
12.Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–1104
13.Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–1109
14.Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 2010;138:1338–13451345.e1-7
15.Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461:798–801
16.Montes-Cano MA, Garcia-Lozano JR, Abad-Molina C, et al. Interleukin-28B genetic variants and hepatitis virus infection by different viral genotypes. Hepatology. 2010;52:33–37
17.Tillmann HL, Thompson AJ, Patel K, et al. A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice. Gastroenterology. 2010 Jul 14;[epub ahead of print]
18.Yan KK, Guirgis M, Dinh T, et al. Treatment responses in Asians and Caucasians with chronic hepatitis C infection. World J Gastroenterol. 2008;14:3416–3420
19.Liu CH, Liu CJ, Lin CL, et al. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial. Clin Infect Dis. 2008;47:1260–1269
20.Mangia A, Thompson AJ, Santoro R, et al. An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response. Gastroenterology. 2010;139:821–827
21.Rallon NI, Naggie S, Benito JM, et al. Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients. AIDS. 2010;24:F23–F29
22.Martin MP, Qi Y, Goedert JJ, et al. IL28B polymorphism does not determine hepatitis B virus or HIV outcomes. J Infect Dis (in press).
23.Kamatani Y, Wattanapokayakit S, Ochi H, et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet. 2009;41:591–595
24.Fellay J, Shianna KV, Ge D, et al. A whole-genome association study of major determinants for host control of HIV-1. Science. 2007;317:944–947
25.Thompson AJ, Muir AJ, Sulkowski MSet a. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139:120–129
26.Honda M, Sakai A, Yamashita T, et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of interferon therapy for chronic hepatitis C. Gastroenterology. 2010;139:499–509
27.Chen L, Borozan I, Feld J, et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology. 2005;128:1437–1444
28.Sarasin-Filipowicz M, Oakeley EJ, Duong FH, et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci U S A. 2008;105:7034–7039
29.Ank N, West H, Paludan SR. IFN-lambda: novel antiviral cytokines. J Interferon Cytokine Res. 2006;26:373–379
30.Sommereyns C, Paul S, Staeheli P, et al. IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. 2008;4:e1000017
31.Jordan WJ, Eskdale J, Srinivas S, et al. Human interferon lambda-1 (IFN-lambda1/IL-29) modulates the Th1/Th2 response. Genes Immun. 2007;8:254–261
32.Srinivas S, Dai J, Eskdale J, et al. Interferon-lambda1 (interleukin-29) preferentially down-regulates interleukin-13 over other T helper type 2 cytokine responses in vitro. Immunology. 2008;125:492–502
33.Morrow MP, Pankhong P, Laddy DJ, et al. Comparative ability of IL-12 and IL-28B to regulate Treg populations and enhance adaptive cellular immunity. Blood. 2009;113:5868–5877
34.Onoguchi K, Yoneyama M, Takemura A, et al. Viral infections activate types I and III interferon genes through a common mechanism. J Biol Chem. 2007;282:7576–7581
35.Mordstein M, Kochs G, Dumoutier L, et al. Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog. 2008;4:e1000151
36.Mordstein M, Neugebauer E, Ditt V, et al. Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J Virol. 2010;84:5670–5677
37.Ank N, West H, Bartholdy C, et al. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol. 2006;80:4501–4509
38.Dellgren C, Gad HH, Hamming OJ, et al. Human interferon-lambda3 is a potent member of the type III interferon family. Genes Immun. 2009;10:125–131
39.Doyle SE, Schreckhise H, Khuu-Duong K, et al. Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology. 2006;44:896–906
40.Hou W, Wang X, Ye L, et al. Lambda interferon inhibits human immunodeficiency virus type 1 infection of macrophages. J Virol. 2009;83:3834–3842
41.Ank N, Iversen MB, Bartholdy C, et al. An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity. J Immunol. 2008;180:2474–2485
42.Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2009;494:1335–1374
43.Grebely J, Petoumenos K, Hellard M, et al. Potential role for interleukin-28B genotype in treatment decision-making in recent hepatitis C virus infection. Hepatology. 2010;52:1216–1224
44.Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology. 2010;52:421–429
45.Thio CL, Thomas DL. Interleukin-28b: a key piece of the hepatitis C virus recovery puzzle. Gastroenterology. 2010;138:1240–1243
Conflicts of interest The authors disclose no conflicts.
Funding Supported by National Institutes of Health grants DA13324 and 1K08AI081544.
PII: S0016-5085(10)01462-9
doi:10.1053/j.gastro.2010.10.004
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Volume 139, Issue 6 , Pages 1865-1876, December 2010
Ashwin Balagopal, David L. Thomas, Chloe L. Thio
Received 6 August 2010; accepted 8 October 2010. published online 14 October 2010.
John P. Lynch and David C. Metz, Section Editors
Treatment-induced control and spontaneous clearance of hepatitis C virus (HCV) infection are affected by various host factors. Polymorphisms in the region of the gene IL28B are associated with HCV clearance, implicating the gene product, interferon (IFN)-λ3, in the immune response to HCV. Although it is not clear how the IL28B haplotype affects HCV clearance, IFN-λ3 up-regulates interferon-stimulated genes, similar to IFN-α and IFN-β but via a different receptor. There is also evidence that IFN-λ3 affects the adaptive immune response. The IL28B genotype can be considered, along with other factors, in predicting patient responses to therapy with pegylated IFN-α and ribavirin. We review the genetic studies that uncovered the association between IL28B and HCV clearance, the biology of IFN-λ3, the clinical implications of the genetic association, and areas of future research.
Keywords: IL28B, Hepatitis C Virus, Interferon Lambda, Interferon Sensitivity, HCV Treatment
Abbreviations used in this paper: GWAS, genome-wide association studies, HIV, human immunodeficiency virus, IFN, interferon, IL-10Rβ, interleukin-10 receptor beta chain, IL-28Rα, interleukin-28 receptor alpha chain, ISG, interferon-stimulated gene, PEG, pegylated, RBV, ribavirin, SNP, single nucleotide polymorphism, STAT, signal transducers and activators of transcription, SVR, sustained virologic response
Spontaneous clearance of hepatitis C virus (HCV) occurs in ∼30% of patients with acute infections; the remaining patients develop chronic infections and have predispositions to cirrhosis and hepatocellular carcinoma.1, 2, 3 Among chronically infected patients, HCV can be cleared by interferon (IFN)-α–based treatment in some cases. Researchers have searched for factors responsible for natural and treatment-induced HCV clearance for more than 10 years. In the past year, genetic studies have identified several single nucleotide polymorphisms (SNPs) in and near IL28B (which encodes IFN-λ3) that are associated with clearance. We review the role of IL28B in HCV infection, clinical implications, and directions for future research.
Overview of the IFN-λ Family
IFN-λ3 belongs to the IFN-λ family, along with IFN-λ1 and IFN-λ2, which are encoded by IL29 and IL28A, respectively. IFN-λs are categorized as type 3 IFNs and are potent, endogenous antiviral cytokines. Although they are structurally most homologous to members of the IL10 family, IFN-λs are more functionally similar to type 1 IFNs4; they signal via Jak/signal transducers and activators of transcription (STAT) intracellular pathways and up-regulate transcription of IFN-stimulated genes (ISGs) that are required to control viral infection. IFN-λ–like sequences have been found in most mammalian species, but many are pseudogenes.5 Phylogenetic studies of type 1 and type 3 IFNs and the interleukin-10 family of cytokines indicate the existence of a common, ancestral IFN gene that shared the multi-exon genomic structure of the IFN-λ family members; it was putatively identified in ancient fish, evolved in a series of gene duplication and retrotransposon events, and gave rise to the IFNs observed in mammals.5 In humans, the IFN-λ genes cluster on chromosome 19 (Figure 1).5
IFN-λs inhibit HCV replication in vitro,6, 7, 8 and trials of IFN-λ1 in patients with chronic HCV infections have shown promising results9; 86% of treatment naive-patients who received combined pegylated (PEG) IFN-λ and ribavirin (RBV) for 4 weeks had a >2 log10 IU/mL decrease in HCV RNA. Therefore, associations made between IL28B variants and HCV clearance in large-scale genetic studies provide an exciting mechanistic link between innate immunity and viral clearance.
IL28B and Control of HCV Infection With Therapy
Many of the first studies that linked IL28B and HCV clearance came from studies of large cohorts of patients with chronic HCV infection who were treated with PEG-IFN-α and RBV. These cohorts were investigated in genome-wide association studies (GWAS), which allow an unbiased sampling of variations in genes across the entire genome without a hypothesis. The first GWAS was performed using an Illumina Human610Quad BeadChip (San Diego, CA) in the IDEAL study, in which patients infected with HCV genotype 1 were randomly assigned to groups that were treated with PEG-IFN-α2a or PEG-IFN-α2b; the study included only subjects who were treated with a minimum number of total doses.10 Although more than 500,000 SNPs were considered, the investigators found that the strongest predictor of sustained virologic response (SVR) was a SNP (rs12979860) located on the long arm of chromosome 19, within the IFN-λ gene cluster (Figure 2). IL28B is upstream and in the reverse orientation of IL28A; rs12979860 is upstream of both of these genes, closer to IL28B (Figure 1). At this position, the C allele is the most frequently observed in the white population (but not in the black population) and is associated with SVR; people with the CC genotype have SVR rates more than 2-fold higher than those with the minor T allele (Table 1). In addition to this SNP, the 6 SNPs most strongly associated with SVR were also found at the IFN-λ gene cluster, although the effects of these were no longer observed after adjusting for the presence of rs12979860. After adjusting for the association of rs12979860, the next SNP most strongly associated with SVR found in the GWAS was rs8099917, a noncoding SNP found ∼7.5 kilobases upstream of the IL28B start codon. These findings were validated in a study that genotyped the rs12979860 SNP in patients from the Duke Hepatology Clinical Research Database and Respository, a registry of patients with HCV infections who were followed up longitudinally.11 The subjects had HCV genotype 1 (80.5%) or genotype 2 or 3 (19.5%) infections and had received complete courses of PEG-IFN-α and RBV therapy. White subjects, who made up most of the study group, with the CC genotype were >5 times more likely to achieve an SVR than subjects with the CT or TT genotypes (P = 9.0 × 10−6). Differences in treatment outcomes among black subjects were not significantly associated with the IL28B genotype, although the investigators acknowledged the limited power of the study given the smaller numbers of black subjects included (n = 106). The association of IL28B genotype with SVR was independent of treatment history. In contrast to treatment response, relapse was not associated with IL28B genotype.
Three other groups used similar approaches to study the genetic basis for SVR and found a group of SNPs near IL28B that were in strong linkage disequilibrium, indicating that they were inherited as a block rather than independently. Depending on the technology used and the racial composition of the study population, the specific findings of each study varied (detailed in the following text; Figure 1 and Table 1). Collectively, the results showed that there is a genomic region comprising IL28B and its potential regulatory sequences that is strongly associated with IFN response (Figure 3). Suppiah et al studied Australians of European descent with HCV genotype 1 infections who received PEG-IFN-α and RBV.12 In the first phase, a GWAS was performed on all participants and results were compared between patients who achieved an SVR while receiving treatment and those who did not respond. Several SNPs were associated with clearance, but the strongest was rs8099917. Compared with the T allele, heterozygosity for the minor G allele was associated with a 1.64-fold increase in risk for not responding to therapy and homozygosity was associated with a 2.39-fold increase in risk.
Tanaka et al performed a GWAS using an Affymetrix SNP Array (Santa Clara, CA) of DNA from HCV genotype 1–infected Japanese patients who achieved an SVR to therapy with PEG-IFN-α2a or PEG-IFN-α2b and RBV, comparing data with that of nonresponders.13 The SNPs rs8099917 and rs12980275 segregated with treatment response (Figure 1). Rauch et al performed a GWAS of the Swiss Hepatitis C Cohort, a population of European white subjects infected with HCV genotypes 1 (48%), 2 (10%), 3 (29%), and 4 (9%) who received PEG-IFN-α and RBV.14 The most significant markers were clustered at the IFN-λ gene loci. The SNP rs8099917 was most highly associated with response to treatment, also reported by Suppiah et al and Tanaka et al (Figure 1). Only 73.9% of patients homozygous for the T allele achieved an SVR, but patients with the minor G allele were 5-fold less likely to respond to therapy (P = 3.11 × 10−8). It is important to note that these investigators used different GWAS platforms than Ge et al10 (Figure 1). The rs12979860 was associated with SVR in subsequent studies, but this association was not fully tested; Tanaka et al did not include rs12979860 in their GWAS platform, and Suppiah et al and Rauch et al used multiple platforms with only limited representation of this SNP. Rauch et al did report that where data were available for rs12979860 it was linked to rs8099917.
IL28B Mapping and HCV Control
It appears that an IL28B haplotype can be a strong determinant of a patient's response to treatment of HCV infection and can be represented by a single SNP (or a small number of SNPs) (Figure 3). Several groups performed more finely tuned genetic studies to clarify which SNP(s) had the greatest associations with treatment response. Ge et al sequenced the IL28B gene in a subset of patients to find genetic markers that were in high linkage disequilibrium with the SNP rs12979860, identified in their GWAS.10 Two additional markers were found: a nonsynonymous SNP (rs8103142) within the IL28B gene that encodes a lysine → arginine substitution at position 70 (K70R) and a G → C substitution (rs28416813) 37 base pairs upstream of the translation initiation site (Figure 1). These 3 SNPs were tightly linked, so it was a challenge to associate any one, individually, with treatment response. Suppiah et al genotyped 20 additional SNPs within the IL28B gene in an expanded cohort that included white subjects from Europe and Australia and compared frequencies between subjects who did and did not achieve an SVR.12 A G allele at rs12980275 had the strongest association with nonresponse (Figure 2). In this study, a 6-allele haplotype was identified that also included K70R (T > C on the coding strand); the haplotype with an arginine (R) was associated with nonresponse.
Similarly, Tanaka et al sequenced 16 SNPs in a validation cohort, based on HapMap data that characterized chromosome 19.13 Although they associated the haplotype, which included K70R, with response to therapy, it did not have a significantly greater association with SVR than any of the individual SNPs; thus, any single SNP is sufficient to mark the association with an SVR. In a logistic regression model, rs8099917 was most predictive of an SVR. Rauch et al sequenced the IL28B gene in subjects with the TT genotype at rs8099917 (associated with response) who achieved the expected SVR and those who did not achieve an SVR (the unexpected outcome).14 They also sequenced DNA from subjects with the risk GG genotype with the expected outcome of nonresponse to therapy and from those who achieved an SVR despite carrying this genotype. Twenty-one additional SNPs were identified that fell into 1 of 2 haplotype families. The first family was associated with HCV clearance, and the second was associated with persistence. As with Suppiah et al, an R at amino acid position 70 was found in the risk haplotype, along with another SNP (rs28416813) identified by Ge et al.10, 12, 14 These genetic mapping studies identified the specific alleles associated with response (or lack of response) to anti-HCV therapy (Figure 3).
IL28B and Spontaneous Clearance
The same IL28B haplotypes associated with treatment response are also associated with spontaneous clearance of HCV. Thomas et al genotyped the rs12979860 SNP in more than 1000 people from 6 cohorts with well-characterized spontaneous clearance of HCV or viral persistence and found that the CC genotype was strongly associated with HCV clearance (odds ratio, 0.33; P < 10−12).15 The investigators also showed that the clearance was mediated by linkage of this genotype with other identified markers, because their inclusion in a multivariate model did not reduce the association between the CC genotype and viral clearance. Ge et al had observed the clearance effect of the C allele at a higher frequency (73%) in a population with unknown HCV status compared with patients with chronic infections who went on to receive treatment (63%; P = 2.48 × 10−6), suggesting that this allele occurred more frequently among patients with spontaneous clearance of HCV.10 Further evidence that IL28B is involved in spontaneous clearance was provided by Rauch et al using a GWAS.14 They associated the T allele of rs8099917 with spontaneous clearance; no SNPs outside the IL28B/A gene loci were associated with clearance. In studies of a cohort of Spanish patients with acute HCV infection and a cohort of German patients with acute HCV infections (from the anti-D common source outbreak), researchers reported that the CC genotype at rs12979860 was observed more frequently in subjects with spontaneous resolution of HCV.16, 17 These results indicate the involvement of the same IL28B SNPs in both spontaneous and treatment-induced control of HCV infection (Figure 3).
IL28B and Racial Differences in HCV Control
Because SNPs in IL28B have varied distributions among ethnic groups (Table 2; http://www.hapmap.org/), it is intriguing to consider whether the differences at this locus account for the association between white ethnicity and increased spontaneous and treatment-induced clearances. Of the 2 alleles most strongly associated with HCV clearance (rs12979860 C and rs8099917 T), only the former is more common in people of European compared with African descent (Table 2 and Figure 4; hapmap.org); it might underlie the racial differences observed. Thomas et al genotyped the rs12979860 SNP in more than 2000 people from 51 ethnic populations worldwide and showed that East Asian populations have the highest frequencies of the alleles associated with clearance, sub-Saharan African populations have the lowest frequencies, and European populations have intermediate frequencies (Figure 4).15 In their study population, Ge et al also found the lowest frequencies of the allele associated with clearance among black subjects (allele frequency, ∼0.42), the highest frequencies in East Asian subjects (∼0.95), and intermediate frequencies in European-American (∼0.73) and Hispanic (∼0.7) subjects; these findings were validated in a subsequent study.10, 11 This distribution of alleles could account for the high rates of treatment-induced SVR observed in East Asian subjects.18, 19 When this SNP was studied in multivariate models of spontaneous and treatment-induced clearance, however, it accounted for only ∼50% to 60% of the ethnic differences observed in HCV control (D. L. Thomas, personal communication, August, 2010).10 It is notable that only 53% of black subjects with this genotype achieved an SVR compared with 82% of white subjects. Other genetic factors beyond IL28B genotype mediate spontaneous and treatment-associated clearance of HCV, although within a given race, IL28B genotype does predict outcome.
IL28B in HCV Genotype 2 and 3 Infections
Most of the initial studies of IL28B and HCV control were centered on people with HCV genotype 1 infections; studies of IL28B in patients infected with HCV of other genotypes have produced conflicting data and included small numbers. The largest study included 268 subjects infected with HCV genotype 2/3 who were randomly assigned to groups that were given PEG-IFN-α and RBV for a standard (24 weeks) or variable duration (12 weeks if they had a rapid virologic response or 24 weeks if they did not).20 Surprisingly, the genotype of IL28B was not associated with SVR in subjects who received standard duration therapy or who achieved a rapid virologic response and received variable therapy (12 weeks). There was a strong association between IL28B and treatment response only among subjects who did not achieve a rapid virologic response and received variable therapy (24 weeks). Intriguingly, in this subset, there appeared to be an effect of gene dose; IL28B heterozygotes had an intermediate rate of SVR, between that of patients with homozygosity for alleles that were and were not associated with clearance.
Several other studies have produced mixed results. Montes-Cano et al associated the IL28B haplotype with an SVR in a cohort of Spanish patients with non–genotype 1 infections.16 McCarthy et al found that the effect of the IL28B haplotype on SVR was similar between subjects with HCV genotypes 1 and 2/3.11 The inclusion of IL28B genotype in a multivariate model, however, reduced only slightly the influence of HCV genotype on SVR. In contrast, Rauch et al noted a trend in the effect of the IL28B haplotype in subjects infected with HCV genotypes 2/3, but this was not statistically significant,14 whereas Rallon et al did not associate the IL28B haplotype with treatment response in people infected with HCV genotype 3.21 The effect of the IL28B haplotype status on treatment response might therefore be attenuated for genotypes 2 and 3, but further research is required to clarify this relationship.
IL28B in Patients Coinfected With Human Immunodeficiency Virus and HCV
About one third of people infected with human immunodeficiency virus (HIV) are also infected with HCV. HIV complicates HCV infection by increasing rates of HCV persistence.2 Despite the immunologic changes associated with HIV infection, it does not affect the association between SNPs near the IFN-λ gene cluster and clearance of HCV. Thomas et al reported that stratification based on HIV status did not modulate the effect of the SNP rs12979860 on HCV clearance.15 Similarly, in a subset of patients in the Swiss Hepatitis C Cohort who were infected with HIV, Rauch et al found that the SNP rs8099917 was still associated with HCV clearance; effects of this SNP did not differ markedly between HCV-infected patients with or without HIV infection.14 Rallon et al found that among patients coinfected with HIV and HCV who completed PEG-IFN-α and RBV treatment, the CC genotype at locus rs12979860 was associated with an SVR and the association was strongest among patients infected with HCV genotypes 1 or 4.21 Given the low rates of spontaneous clearance and treatment-induced SVR among people coinfected with HIV and HCV, it is striking that IL28B is still associated with HCV control in this population.
IL28B and Other Infectious Diseases
Martin et al investigated whether IL28B SNPs are important in the control of other chronic viral infections where IFN-α is important in the immune response.22 A cohort of 226 individuals with persistent hepatitis B virus (HBV) infection was compared with 384 individuals who had recovered from HBV infection; recovery was not associated with the rs12979860 SNP. They also studied a cohort of 2548 individuals with, or who were at high risk for, HIV infection and found that the rs12979860 SNP was not associated with infection with HIV or disease progression. In GWAS with the Illumina HumanHap550 BeadChip, Kamatani et al studied patients with chronic HBV infection and found no association of chronic infection with IL28B genotype.23 Similarly, Fellay et al studied HIV-infected subjects using the Illumina BeadChip and found no association of IL28B with either HIV-1 viral RNA set point or with disease progression.24 Polymorphisms in IL28B have therefore not been associated with clearance of other viral infections.
The Effect of IL28B on HCV RNA Levels, Viral Kinetics, and IFN Responsiveness
Several groups have studied the correlation of IL28B genotype, baseline levels of HCV RNA, and treatment response. Ge et al found that although the C allele of rs12979860 was associated with SVR, it was also, paradoxically, associated with higher viral RNA levels compared with the T allele (CC patients had 6.35 log10 IU/mL, TC patients had 6.33 log10 IU/mL, and TT patients had 6.16 log10 IU/mL; P = 1.21 × 10−10).10 Higher levels of HCV RNA levels were also observed in patients who were off therapy who had the C allele.11 Although the differences are modest (<0.5 log10), the higher levels of HCV RNA among patients with the CC genotype might facilitate innate immune detection and control of the virus during treatment.
In addition to baseline level of HCV RNA, the kinetics of the treatment response appears to be influenced by IL28B genotype. Thompson et al compared viral kinetic data between subjects with CC, CT, and TT genotypes at the rs12979860 SNP 2 weeks after they began therapy with PEG-IFN-α and RBV.25 Irrespective of race, subjects with the CC genotype had the largest reductions in levels of HCV RNA (white subjects with CC genotype had the greatest decrease in HCV RNA). This translated to greater rapid virologic response and early virologic response rates among subjects with the CC genotype. Much of the effect of the IL28B genotype is evident in the first 48 hours after treatment, indicating that IL28B genotype somehow primes the host response to HCV, decreasing the threshold for virologic control with treatment. Alternatively, IL28B genotype could simply be a marker for greater baseline levels of the IFN response, consistent with the findings in patients with spontaneous clearance of HCV.
Intriguingly, Honda et al found that subjects with the TT genotype at the SNP rs8099917 (associated with SVR) had pretreatment hepatic expression levels of ISGs that were lower than those of subjects with the TG or GG genotypes.26 The fact that subjects with genotypes associated with SVR have reduced expression of ISGs might account for the higher levels of HCV RNA observed before treatment. Sensitivity to exogenous IFN is inversely associated with levels of ISGs; IL28B genotypes may affect expression levels of ISGs, accounting for the association between IL28B genotype and response to therapy.27, 28 Despite the association of IL28B with clearance, there are people who carry alleles that are not associated with clearance who clear the virus, as well as patients with alleles associated with clearance whose infection persists. Further studies should be performed with these patients to investigate IL28B genetics, ISG expression levels, and other genetic factors involved in the response to anti-HCV therapy.
IFN-λ Biology and Role in HCV Infection
IL28B can determine the outcome of HCV infection, but the mechanisms that mediate the association between the different SNPs and HCV control are unclear, especially in light of the lack of association of IL28B polymorphisms with HBV or HIV infection outcomes. Investigating the biology of IFN-λ in HCV and other viral infections could provide mechanistic insight.
The main cellular sources of IFN-λs are believed to be plasmacytoid dendritic cells, although macrophages and conventional dendritic cells probably also produce IFN-λs.29 It is not known which cells produce IFN-λs in the liver, but candidates include Kupffer cells, dendritic cells, and liver sinusoidal endothelial cells. Hepatocytes also have active innate immune responses and probably release IFN-λs on viral infection.6, 7 Although IFN-λs have many effects on a number of viruses, their site of action is constrained by expression of their cognate receptor. IFN-λs signal through a heterodimer that comprises the interleukin-28 receptor α chain (IL-28Rα) and the interleukin-10 receptor β chain (IL-10Rβ). In contrast to the distribution of IFN-α receptor and even IL-10Rβ, which are found on a wide variety of cell types, IL-28Rα is found primarily on epithelial cells. This has implications on which cells IFN-λs can act on; in one study, livers from mice were found to express only low levels of IL-28Rα.30
Downstream signaling after IFN-λ receptor ligation, however, is similar to type 1 IFN signaling and occurs via the covalently bound tyrosine kinases Tyk2 and Jak1 (Figure 5).29 These binding partners phosphorylate each other and also phosphorylate STAT1 and STAT2 proteins. A consequence of phosphorylation of STAT1 and STAT2 is the formation of the IFN-stimulated gene factor 3 complex along with activated IFN-regulatory factor 9, which leads to the up-regulation of canonical ISGs. ISG up-regulation causes many of the innate cellular defenses against viral infection. Overall, IFN-λ signaling is believed to be proinflammatory and unlike responses to IL-10, despite sharing the IL-10 receptor subunit.
In addition to phosphorylation of STAT1 and STAT2, STAT3, STAT4, and STAT5 can also be activated via the IL-10Rβ chain, which can have immunomodulatory effects.29 IFN-λ1 and IFN-λ2 inhibit IL-13 production by T cells following stimulation with concanavalin A, indicating that IFN-λs promote the T-helper cell 1 response.31, 32 IFN-λ3 increases the T-helper cell 1 response to an HIV DNA vaccine and simultaneously inhibits regulatory T-cell responses.33 More investigations into the effect of IFN-λs on adaptive immunity could reveal that HCV control by IFN-λ is the result of a multi-level response.
It is not clear how the SNPs in IL28B affect the IFN signaling pathways. The rs12979860 is 3 kilobases upstream of IL28B, whereas rs8099917 is nearly 8 kilobases upstream (Figure 1). Although it is possible that these SNPs modulate IL28B transcription, it is more likely that they are in linkage disequilibrium with one or more SNPs in the IL28B coding or promoter regions. Alternatively, the SNPs could modify transcription factor binding sites. IL29 has multiple IFN-regulatory factor and nuclear factor κB binding sites (eg, −214 to −172 and −98 to −89 upstream of the transcription initiation site), although those that have been reported are not polymorphic.34 The SNP that encodes K70R is important to study because it is tightly linked with SNPs associated with SVR and natural clearance. K70R is not predicted to affect binding to the receptor or signaling, but it could be involved in interactions with other signaling factors that affect viral control.4 The SNPs in IL28B might lead to expression of forms of IFN-λ3 that do not function or have weak function or even hyperfunctional variants that reduce the antiviral response by negative feedback. Research is required to determine how IL28B and its variants affect HCV persistence and response to therapy.
Because IFN-λs inhibit viral replication, it is logical to consider that expression of different amounts of endogenous IFN-λ3 could determine whether a patient controls the virus or remains infected. Two studies compared messenger RNA levels of IFN-λ in whole blood or peripheral blood mononuclear cells from subjects with the T allele at position rs8099917 (associated with clearance) with that of subjects with the G allele (associated with viral persistence).12, 13 It has been difficult to quantify IFN-λ2 and IFN-λ3 messenger RNA levels by polymerase chain reaction because of their sequence homology; levels of IFN-λ2 and IFN-λ3 measured by quantitative polymerase chain reaction are combined when reported. Each group found the highest expression of IFN-λ2 and IFN-λ3 in subjects with the TT genotype, compared with TG and GG genotypes, associating higher amounts of endogenous IFN-λs with HCV clearance. Using information from the SNPExpress database, Ge et al, in contrast, did not observe differences in IFN-λ3 expression among subjects not infected with HCV who were homozygous for an allele in linkage disequilibrium with the rs12979860 SNP (see supplemental data for Ge et al).10 Similarly, Honda et al found no association between hepatic expression of IFN-λ2 and IFN-λ3 and rs8099917 genotype.26 Studies of plasmacytoid dendritic cells and cells that produce IFN-λ in the liver should provide insight into the relationship between the IL28B genotype and expression.
Studies of animals with viral infections indicate that the organ-specific distribution of IL-28Rα determines response to IFN-λ. While some studies observed that IFN-λ protects mice against respiratory but not hepatic viruses,35, 36 others found protection against hepatic viral infection.37 One study made the surprising observation that IFN-λ did not induce expression of ISGs in livers of mice.30 Studies in mice should be interpreted cautiously, however; in human cells and tissues, IFN-λ expression was shown to affect hepatotropic viruses. Robek et al found that IFN-λ1 and IFN-λ2 inhibited HBV replication.6 Moreover, recombinant IFN-λ3 had a more potent antiviral effect than IFN-λ1 or IFN-λ2 against encephalomyocarditis virus in hepatocyte cell lines.38 There has not been an extensive, published study of whether primary human hepatic cells respond to IFN-λ, although in one report HCV-infected liver tissue had higher amounts of IL-28Rα than uninfected liver tissue.39 Interestingly, treatment of macrophages with IFN-λ1 inhibited HIV-1 infection, possibly through production of competitive ligands for HIV coreceptors; it is not clear how this finding might relate to HCV clearance in patients.40
Several in vitro studies support a direct role for IFN-λ for the control of HCV replication through the innate immune pathway. Robek et al showed that subgenomic and full-length HCV replicons were inhibited by recombinant IFN-λ1 and IFN-λ2, which up-regulated a representative ISG.6 In a cell culture system, Marcello et al7 showed that IFN-λ1 inhibited HCV replication with similar kinetics to that of IFN-α but that IFN-λ1–induced up-regulation of ISGs was stronger and lasted longer. Combinations of IFN-λ1 and IFN-α had the greatest inhibitory effect on HCV replication compared with individual agents.8 IFN-λ and IFN-α might therefore have synergistic effects in controlling HCV infection. Type 1 IFN potentiated IFN-λ release in an animal model of viral infection.41 It is possible that the putative SNPs alter the interaction of IFN-λ with IFN-α.
Clinical Implications
The IL28B genotype provides important, independent information about a patient's likelihood of achieving an SVR, and a commercial test became available in the United States in July 2010. Results from this test could be used in combination with algorithms based on HCV genotype and viral load to predict patients' responses to treatment; IL28B genotype could be a factor that patients and their physicians use to decide whether to initiate therapy or wait until direct antiviral agents become available. Unfortunately, IL28B genotype does not have a positive predictive value of 100% for SVR, so it cannot be used as the only predictor of response (Table 1); HCV treatment should not be withheld based solely on IL28B genotype. In addition, the positive predictive value is influenced by the prevalence of SVR, which is difficult to extrapolate from published studies in which patients with ambiguous outcomes were removed from the analyses and the proportions of patients that achieve SVRs varied. To put some numbers in perspective, the SVR rate for black subjects with the rs12979860 CC genotype (associated with clearance) was 53%10; this is similar to that of white subjects with genotype 1 HCV, irrespective of IL28B genotype. Among white subjects in the same study, the SVR rate for those with the rs12979860 CC genotype was ∼82%. Interestingly, when the likelihood of SVR approaches 80%, IL28B genotype can also affect the decision for liver disease staging before treatment. Just as patients with genotype 2 or 3 HCV infection can elect to undergo treatment without consideration of fibrosis stage, people who have IL28B genotypes associated with viral control might decide not to undergo biopsy evaluation. In either case, noninvasive staging is still recommended to determine whether patients should be screened for hepatocellular carcinoma.42
IL28B genotype can affect how long a clinician should monitor someone with an acute HCV infection before treatment. Those with a haplotype associated with HCV clearance might be monitored longer, because they are more likely to spontaneously clear the virus; those with haplotypes associated with persistence might be better off receiving therapy during the acute period and be monitored for a shorter period beforehand.43 The association between kinetics of HCV response to IFN treatment and IL28B genotype might be used to identify patients who require shorter durations of therapy; further studies are required to determine if this is the case. The association between sensitivity to IFN therapy and IL28B genotype could also affect how clinicians use direct antiviral agents. For example, IFN lead-in dosing might be the best option for patients with IL28B haplotypes that are not associated with HCV clearance; they are more likely to develop resistance to direct antiviral agents because their response to IFN-α therapy is slower.
As therapeutic agents, IFN-λs might have longer and more potent effects than type 1 IFNs, with fewer adverse events, because distribution of IFN-λ receptors is more restricted. Phase 1 trials of IFN-λ1 in treatment-naive patients and those with chronic HCV who experienced a relapse after therapy have shown significant reductions in HCV viremia after 4 weeks.9 It will be interesting to see if polymorphisms in IL28B predict a response to IFN-λs in these trials; later-stage trials are under way.
Future Directions
Basic science studies help us understand how specific genetic features relate to immunologic function and HCV clearance. It is important to determine exactly which SNP or specific genetic feature of IL28B affects clearance, and this could require sequencing of IL28A and IL29 in different ethnic groups of patients with natural and treatment-induced clearance to understand linkage in this region. Comparing the human IL28B sequence with that of chimpanzees and other primates might also provide important information about linkage. Although the same gene cluster and SNPs are associated with clearance versus persistence and an SVR versus no response to therapy, these gene variants might affect responses via different mechanisms. The structure of IFN-λ3 has been determined, but the active-site amino acids have only been inferred from alanine scans; the role of SNPs in the IL28B coding region might be more precisely defined by resolving the structure of IFN-λ3 bound to its heterodimeric receptor. Investigations into the genetics of HCV control are hampered by inadequate model systems of HCV infection; animals with phenotypes that more closely resemble patients with HCV infection would improve our understanding of the role of IFN-λ3 in HCV infection. Several HCV cell culture systems exist and studies are under way to examine the role of IL28B in HCV replication using site-directed mutagenesis to compare major and minor alleles for several SNPs. Similarly, knockout mice with humanized livers can be used to study the effects of IFN-λ3 on the immune response and HCV control. Because IFN-λs can have redundant effects, responses to IFN-λ might need to be fully suppressed by interfering with IL-28Rα signaling. Using combined approaches, ISG responses to HCV can be determined using cell culture systems, animal models, small interfering RNAs, and antibodies that inhibit IFN-λ signaling.
In situ studies of liver tissues from patients with chronic HCV infection are necessary to delineate which cells release or respond to IFN-λs, especially given findings from mouse studies that hepatic expression of IL28Rα is limited. Studies should be performed in human hepatic tissue to compare expression of IFN-λ with its receptor. IL28B genotype is assumed to predict the early stages of HCV control, but other immunologic factors, such as pretreatment levels of ISG, might also predict response. It will be important to determine whether IL28B SNPs also predict response to small molecule therapeutics, their utility in patients with acute HCV infections, and optimal treatment duration. There is evidence that IL28B is associated with an SVR in subjects with chronic HCV who were treated with the protease inhibitor telaprevir in addition to standard therapy.44 The paradox of the association of IL28B genotypes that promote HCV clearance and higher baseline levels of HCV RNA should be further evaluated; usually patients with poor response to treatment have high pretreatment levels of HCV RNA. IL28B genotype might not predict clearance of all HCV genotypes, and the interaction between host and viral genotypes should be further explored. Interest in IL28B genotype has extended to other chronic viral infections, and researchers are investigating whether genotypes associated with HCV clearance have other effects in the immune response to pathogens. The identification of IL28B heralds the era of genomic medicine in HCV and opens the door to understanding HCV clearance. The finding has spurred intense bidirectional investigation into the clinic and the bench with the hopes of enhanced therapies against HCV. The coming months and years promise rapid fulfillment of some of these goals and healthy excitement in the field.
References
1.Wilson LE, Torbenson M, Astemborski J, et al. Progression of liver fibrosis among injection drug users with chronic hepatitis C. Hepatology. 2006;43:788–795
2.Thomas DL, Astemborski J, Rai RM, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA. 2000;284:450–456
3.Thomas DL, Seeff LB. Natural history of hepatitis C. Clin Liver Dis. 2005;9:383–398vi
4.Gad HH, Dellgren C, Hamming OJ, et al. Interferon-lambda is functionally an interferon but structurally related to the interleukin-10 family. J Biol Chem. 2009;284:20869–20875
5.Fox BA, Sheppard PO, O'Hara PJ. The role of genomic data in the discovery, annotation and evolutionary interpretation of the interferon-lambda family. PLoS One. 2009;4:e4933
6.Robek MD, Boyd BS, Chisari FV. Lambda interferon inhibits hepatitis B and C virus replication. J Virol. 2005;79:3851–3854
7.Marcello T, Grakoui A, Barba-Spaeth G, et al. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology. 2006;131:1887–1898
8.Pagliaccetti NE, Eduardo R, Kleinstein SH, et al. Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit hepatitis C virus replication. J Biol Chem. 2008;283:30079–30089
9.Muir AJ, Shiffman ML, Zaman A, et al. Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection. Hepatology. 2010;52:822–832
10.Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401
11.McCarthy JJ, Li JH, Thompson A, et al. Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. Gastroenterology. 2010;138:2307–2314
12.Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–1104
13.Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–1109
14.Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 2010;138:1338–13451345.e1-7
15.Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461:798–801
16.Montes-Cano MA, Garcia-Lozano JR, Abad-Molina C, et al. Interleukin-28B genetic variants and hepatitis virus infection by different viral genotypes. Hepatology. 2010;52:33–37
17.Tillmann HL, Thompson AJ, Patel K, et al. A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice. Gastroenterology. 2010 Jul 14;[epub ahead of print]
18.Yan KK, Guirgis M, Dinh T, et al. Treatment responses in Asians and Caucasians with chronic hepatitis C infection. World J Gastroenterol. 2008;14:3416–3420
19.Liu CH, Liu CJ, Lin CL, et al. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial. Clin Infect Dis. 2008;47:1260–1269
20.Mangia A, Thompson AJ, Santoro R, et al. An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response. Gastroenterology. 2010;139:821–827
21.Rallon NI, Naggie S, Benito JM, et al. Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients. AIDS. 2010;24:F23–F29
22.Martin MP, Qi Y, Goedert JJ, et al. IL28B polymorphism does not determine hepatitis B virus or HIV outcomes. J Infect Dis (in press).
23.Kamatani Y, Wattanapokayakit S, Ochi H, et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet. 2009;41:591–595
24.Fellay J, Shianna KV, Ge D, et al. A whole-genome association study of major determinants for host control of HIV-1. Science. 2007;317:944–947
25.Thompson AJ, Muir AJ, Sulkowski MSet a. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139:120–129
26.Honda M, Sakai A, Yamashita T, et al. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of interferon therapy for chronic hepatitis C. Gastroenterology. 2010;139:499–509
27.Chen L, Borozan I, Feld J, et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology. 2005;128:1437–1444
28.Sarasin-Filipowicz M, Oakeley EJ, Duong FH, et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci U S A. 2008;105:7034–7039
29.Ank N, West H, Paludan SR. IFN-lambda: novel antiviral cytokines. J Interferon Cytokine Res. 2006;26:373–379
30.Sommereyns C, Paul S, Staeheli P, et al. IFN-lambda (IFN-lambda) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog. 2008;4:e1000017
31.Jordan WJ, Eskdale J, Srinivas S, et al. Human interferon lambda-1 (IFN-lambda1/IL-29) modulates the Th1/Th2 response. Genes Immun. 2007;8:254–261
32.Srinivas S, Dai J, Eskdale J, et al. Interferon-lambda1 (interleukin-29) preferentially down-regulates interleukin-13 over other T helper type 2 cytokine responses in vitro. Immunology. 2008;125:492–502
33.Morrow MP, Pankhong P, Laddy DJ, et al. Comparative ability of IL-12 and IL-28B to regulate Treg populations and enhance adaptive cellular immunity. Blood. 2009;113:5868–5877
34.Onoguchi K, Yoneyama M, Takemura A, et al. Viral infections activate types I and III interferon genes through a common mechanism. J Biol Chem. 2007;282:7576–7581
35.Mordstein M, Kochs G, Dumoutier L, et al. Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog. 2008;4:e1000151
36.Mordstein M, Neugebauer E, Ditt V, et al. Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J Virol. 2010;84:5670–5677
37.Ank N, West H, Bartholdy C, et al. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol. 2006;80:4501–4509
38.Dellgren C, Gad HH, Hamming OJ, et al. Human interferon-lambda3 is a potent member of the type III interferon family. Genes Immun. 2009;10:125–131
39.Doyle SE, Schreckhise H, Khuu-Duong K, et al. Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology. 2006;44:896–906
40.Hou W, Wang X, Ye L, et al. Lambda interferon inhibits human immunodeficiency virus type 1 infection of macrophages. J Virol. 2009;83:3834–3842
41.Ank N, Iversen MB, Bartholdy C, et al. An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity. J Immunol. 2008;180:2474–2485
42.Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2009;494:1335–1374
43.Grebely J, Petoumenos K, Hellard M, et al. Potential role for interleukin-28B genotype in treatment decision-making in recent hepatitis C virus infection. Hepatology. 2010;52:1216–1224
44.Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology. 2010;52:421–429
45.Thio CL, Thomas DL. Interleukin-28b: a key piece of the hepatitis C virus recovery puzzle. Gastroenterology. 2010;138:1240–1243
Conflicts of interest The authors disclose no conflicts.
Funding Supported by National Institutes of Health grants DA13324 and 1K08AI081544.
PII: S0016-5085(10)01462-9
doi:10.1053/j.gastro.2010.10.004
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
UM/Jackson Trial Fights Liver Cancer with Natural Killer Cells
“I feel like a completely new person,’’ Miranda said. “I don’t feel tired. I don’t feel anything. It is remarkable – the difference between how I felt then and how I feel now.’’
The Army veteran from Key Largo owes the difference to the multi-disciplinary team of transplant surgeons, hepatologists, oncologists and interventional radiologists who helped him qualify for the nation’s first clinical trial of the Natural Killer Cell (NK cell) immunotherapy developed at the University of Hiroshima in Japan as a potent weapon against HCC. A growing world epidemic, HCC is most commonly caused by hepatitis C in the U.S. and other western nations.
Liver transplants are now standard therapy for selected HCC patients, but members of the UM/Jackson team know too well that about 20 percent of transplant patients – 15 percent at the Miami Transplant Institute – with primary liver cancer end up dying from a recurrence of the cancer in the replacement liver. The reason, they believe, is that cancer cells remain in the bloodstream even when the tumors are removed or destroyed, or the diseased organ replaced.
So Andreas Tzakis, M.D., Ph.D., professor of surgery and director of the Institute’s Liver/GI Transplant Program, said the team was intrigued by the clinical trial in Japan led by Masahiro Ohira, M.D., Ph.D., that showed naturally occurring NK cells extracted from a healthy liver and enhanced to four times their potency in the lab act like smart bombs. When injected into the bloodstream, they hone in on and destroy any lingering cancer cells. They also have the added bonus of being 10 times more aggressive against the hepatitis C virus.
“You can call them a guided missile versus a smart bomb,’’ Tzakis said. “The important thing is they don’t kill any cells we don’t want them to kill. They kill just tumor cells.’’
In Hiroshima, 22 of 24 transplant patients who received NK cell transfusions after receiving partial livers from live donors remain cancer-free more than three years later.
The goal of the UM/Jackson trial, says David Levi, M.D., professor of clinical surgery and leader of the multidisciplinary team, is to enroll 25 patients and get the recurrence rate “down to zero.’’
Seigo Nishida, M.D., Ph.D., professor of clinical surgery and the trial’s principal investigator, brought the NK cell immunotherapy and Ohira to the Miller School, and secured the funding and FDA approval to begin the UM/Jackson trial. Unlike the Japanese trial, it is testing the cell-based therapy on patients who received livers from deceased donors.
“In Japan, we have few cases of cadaveric donor livers,’’ Ohira said. “So we have collaborated with each other in order to apply this study to cadaveric donor liver transplant in the U.S.’’
But before Miranda could volunteer for the experimental protocol, he had to qualify for a transplant, which he didn’t when the Miami Veteran Affairs Medical Center referred him to the Miller School in October 2009. He had too many tumors in his diseased liver, and they were too advanced.
That’s when the multi-disciplinary team began pulling out other relatively new weapons in their arsenal. Monitored by medical oncologist Jolly Varki, M.D., Miranda underwent specialized chemotherapy in which a catheter was threaded directly into the blood vessel feeding the cancerous liver. But that didn’t work.
So, Govindarajan Narayanan, M.D., chief of interventional radiology, tried burning the tumor with radiofrequency ablation. Inserting a probe heated by radiofrequency electrical current into the tumor, he essentially cooked it.
The next day, he added transarterial chemo embolization to the weaponry. Much like standard chemotherapy, the drug is threaded through the blood vessel. Only this time, the chemo is encapsulated in tiny beads that attack the tumors, a technique that allows the drug to diffuse more slowly, remaining at the tumors a longer period of time.
The tumors soon shrank and Miranda was eligible for the transplant list.
When a donor organ became available, surgeons collected NK cells from the liver, which Ohira enhanced in the lab, and just three days after Miranda’s October 19 transplant, millions of the stimulated NK cells were painlessly injected into his bloodstream.
“Two or three days after the surgery I was already walking and yesterday I walked six miles,’’ Miranda said Thursday. “I have no regrets and I can honestly tell you that today I feel great.’’
As Levi notes, Miranda’s case proves the value of the multi-disciplinary approach, and underscores the need for the kind of tailor-made treatments offered at UM/Jackson.
“There is no one good treatment for this cancer,’’ Levi said. “It’s really the right combination for the right patient that allowed us to achieve the results we are seeing. And it is our hope that the exciting early results of the NK cells will translate into real results in the lowering of the recurrence rate, making what we do from a multi-disciplinary approach even better.’’
Source
European recommendations issued on acute hepatitis C infection in patients with HIV
Michael Carter
Published: 15 December 2010
European investigators and activists have developed recommendations for the management of acute hepatitis C infection in patients with HIV.
Published in the online edition of AIDS, they cover the diagnosis, epidemiology, natural history and treatment of the infection.
It is estimated that approximately a third of HIV-positive patients in Europe are co-infected with hepatitis C. The epidemic of sexually transmitted hepatitis C among HIV-positive gay men has lead to a renewed focus on the infection. Therefore in May 2010 doctors, researchers and activists from a number of European-wide bodies met in Paris to develop consensus guidelines about the management of acute hepatitis C infection.
Their recommendations concerned:
-- Definition of acute hepatitis C infection.
-- Screening for hepatitis C.
-- Risk reduction advice.
-- Natural history.
-- Treatment during acute infection.
Acute hepatitis C is defined as the first six months after infection with the virus. Many people do not develop symptoms when they first contract the virus, and delayed antibody responses have been seen in a minority of HIV-positive patients.
Preferred European criteria for the diagnosis of acute infection are:
1. Positive anti-hepatitis C IgG with or without detectable hepatitis C viral load and a negative hepatitis C antibody test in the previous twelve months.
Or:
2. Positive hepatitis C viral load and a documented hepatitis C negative viral load and negative anti-hepatitis C IgG in the previous year.
However, in circumstances where previous test results are unavailable, acute hepatitis C can be diagnosed if a patient has detectable hepatitis C viral load, with:
1. An increase in ALT levels greater than ten times the upper limit of normal, or five times the upper limit if liver function was normal within the previous twelve months.
2. Negative for both hepatitis A and hepatitis B and all other causes of liver disease have been excluded.
Recommendations are also made concerning the screening of individuals for acute infection. These are:
1. All patients newly diagnosed with HIV should have a hepatitis C antibody test.
2. HIV-positive gay men at risk of hepatitis C should have their ALTs measured every six months and should also have an annual hepatitis C antibody test.
3. Patients with an incident sexually transmitted infection (STI), as well as those who inject drugs, should be screened for acute hepatitis C three months after the diagnosis of the STI or the last possible exposure to the virus.
4. Individuals with suspected acute infection are recommended to have a their hepatitis C viral load monitored using nucleic acid testing.
There is currently some uncertainty about the exact mode of hepatitis C transmission in HIV-positive gay men. However, the following risk-reduction recommendations are made:
1. Advice should include discussions of hepatitis C transmission and fisting, recreational drug use, group sex, use of sex toys, unprotected sex, traumatic sex, sharing injecting equipment, and risks from blood-to-blood contact.
2. Information about hepatitis C risk reduction should be given to all HIV-positive individuals after their diagnosis and then at regular intervals. Patients with newly diagnosed hepatitis C should also be counselled about risk reduction.
A proportion of individuals naturally clear hepatitis C infection without the need for treatment. The consensus recommendations made the following observations about the natural history of the infection:
1. HIV-positive patients are at greater risk of developing chronic hepatitis C infection.
2. Studies suggest that between 0% and 40% of HIV-positive patients spontaneously clear hepatitis C during the acute phase.
3. Factors associated with spontaneous clearance include female sex; sexual transmission; infection with hepatitis B; jaundice; and higher peak ALT levels.
4. An early decline in hepatitis C viral load, four to eight weeks after infection is also associated with spontaneous clearance.
Good response rates to hepatitis C therapy have been seen in HIV-positive patients who start such treatment within a year of contracting the virus. Therefore recommendations are offered regarding the monitoring of the infection and test results that should act as a prompt to initiate treatment.
1. Hepatitis C viral load should be measured when a patient is first diagnosed and then four weeks later.
2. Treatment should be offered if viral load has not fallen by 2 log10 copies/ml at the four week monitoring interval, or if a patient still has a detectable hepatitis viral load twelve weeks after acute infection was diagnosed.
3. In circumstances where patients spontaneously clear the virus, a repeat measurement of viral load should be made after 48 weeks.
Reference
Rockstroh JK. Acute hepatitis C in HIV-infected individuals – recommendations from the NEAT consensus conference. AIDS 25 (online edition), DOI: 10. 1097/QAD.0b013e328343443b, 2010 (click here for the free abstract).
Source
Published: 15 December 2010
European investigators and activists have developed recommendations for the management of acute hepatitis C infection in patients with HIV.
Published in the online edition of AIDS, they cover the diagnosis, epidemiology, natural history and treatment of the infection.
It is estimated that approximately a third of HIV-positive patients in Europe are co-infected with hepatitis C. The epidemic of sexually transmitted hepatitis C among HIV-positive gay men has lead to a renewed focus on the infection. Therefore in May 2010 doctors, researchers and activists from a number of European-wide bodies met in Paris to develop consensus guidelines about the management of acute hepatitis C infection.
Their recommendations concerned:
-- Definition of acute hepatitis C infection.
-- Screening for hepatitis C.
-- Risk reduction advice.
-- Natural history.
-- Treatment during acute infection.
Acute hepatitis C is defined as the first six months after infection with the virus. Many people do not develop symptoms when they first contract the virus, and delayed antibody responses have been seen in a minority of HIV-positive patients.
Preferred European criteria for the diagnosis of acute infection are:
1. Positive anti-hepatitis C IgG with or without detectable hepatitis C viral load and a negative hepatitis C antibody test in the previous twelve months.
Or:
2. Positive hepatitis C viral load and a documented hepatitis C negative viral load and negative anti-hepatitis C IgG in the previous year.
However, in circumstances where previous test results are unavailable, acute hepatitis C can be diagnosed if a patient has detectable hepatitis C viral load, with:
1. An increase in ALT levels greater than ten times the upper limit of normal, or five times the upper limit if liver function was normal within the previous twelve months.
2. Negative for both hepatitis A and hepatitis B and all other causes of liver disease have been excluded.
Recommendations are also made concerning the screening of individuals for acute infection. These are:
1. All patients newly diagnosed with HIV should have a hepatitis C antibody test.
2. HIV-positive gay men at risk of hepatitis C should have their ALTs measured every six months and should also have an annual hepatitis C antibody test.
3. Patients with an incident sexually transmitted infection (STI), as well as those who inject drugs, should be screened for acute hepatitis C three months after the diagnosis of the STI or the last possible exposure to the virus.
4. Individuals with suspected acute infection are recommended to have a their hepatitis C viral load monitored using nucleic acid testing.
There is currently some uncertainty about the exact mode of hepatitis C transmission in HIV-positive gay men. However, the following risk-reduction recommendations are made:
1. Advice should include discussions of hepatitis C transmission and fisting, recreational drug use, group sex, use of sex toys, unprotected sex, traumatic sex, sharing injecting equipment, and risks from blood-to-blood contact.
2. Information about hepatitis C risk reduction should be given to all HIV-positive individuals after their diagnosis and then at regular intervals. Patients with newly diagnosed hepatitis C should also be counselled about risk reduction.
A proportion of individuals naturally clear hepatitis C infection without the need for treatment. The consensus recommendations made the following observations about the natural history of the infection:
1. HIV-positive patients are at greater risk of developing chronic hepatitis C infection.
2. Studies suggest that between 0% and 40% of HIV-positive patients spontaneously clear hepatitis C during the acute phase.
3. Factors associated with spontaneous clearance include female sex; sexual transmission; infection with hepatitis B; jaundice; and higher peak ALT levels.
4. An early decline in hepatitis C viral load, four to eight weeks after infection is also associated with spontaneous clearance.
Good response rates to hepatitis C therapy have been seen in HIV-positive patients who start such treatment within a year of contracting the virus. Therefore recommendations are offered regarding the monitoring of the infection and test results that should act as a prompt to initiate treatment.
1. Hepatitis C viral load should be measured when a patient is first diagnosed and then four weeks later.
2. Treatment should be offered if viral load has not fallen by 2 log10 copies/ml at the four week monitoring interval, or if a patient still has a detectable hepatitis viral load twelve weeks after acute infection was diagnosed.
3. In circumstances where patients spontaneously clear the virus, a repeat measurement of viral load should be made after 48 weeks.
Reference
Rockstroh JK. Acute hepatitis C in HIV-infected individuals – recommendations from the NEAT consensus conference. AIDS 25 (online edition), DOI: 10. 1097/QAD.0b013e328343443b, 2010 (click here for the free abstract).
Source
The Human Fetal Immune Response to Hepatitis C Virus Exposure in Utero
Journal of Infectious Diseases
203, 2
Pp. 196-206.
Jennifer M. Babik 1,2, Deborah Cohan 3, Alexander Monto 4, Dennis J. Hartigan-O'Connor 1 and Joseph M. McCune 1
+ Author Affiliations
1 Division of Experimental Medicine
2 Division of Infectious Diseases, Department of Medicine, University of California, San Francisco
3 Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco and San Francisco General Hospital
4 Division of Gastroenterology, Department of Medicine, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, California
Reprints or correspondence: Dr Joseph M. McCune, Division of Experimental Medicine, Department of Medicine, Box 1234, University of California, San Francisco, San Francisco, CA 94143-1234 (mike.mccune@ucsf.edu).
Abstract
Background. Although the rate of mother-to-child transmission of hepatitis C virus (HCV) is low, the effect of HCV exposure in utero on the fetal immune system is unknown.
Methods. Umbilical cord blood was obtained from 7 neonates born to HCV-seropositive, HCV RNA-positive women and 8 neonates born to HCV-seronegative women. Cord blood mononuclear cells were analyzed by immunophenotyping and by intracellular cytokine staining after HCV-specific and polyclonal stimulation. Plasma was analyzed for anti-HCV immunoglobulin M (IgM), cytokine/granzyme concentrations, and indoleamine 2,3-dioxygenase (IDO) activity.
Results. HCV-exposed neonates had significantly lower levels of regulatory T cells expressing HLA-DR, lower CD4+ and CD8+ T cell activation, and lower plasma levels of pro-inflammatory markers than did controls. However, CD4+ and CD8+ T cells from HCV-exposed neonates had higher IFN-γ production in response to polyclonal stimulation than did T cells from controls. IDO activity was similar between groups. No HCV-specific T cell responses or anti-HCV IgM were detected in any neonates.
Conclusions. HCV-exposed neonates showed a relative suppression of immune activation and pro-inflammatory markers, which was counterbalanced by an increased production capacity for IFN-γ. These results suggest that HCV encounters the fetal immune system in utero, and alters the balance between suppressive and pro-inflammatory responses.
Footnotes
Potential conflicts of interest: none reported.
Financial support: This work was supported in part by a Ruth L. Kirschstein National Research Service Award (T32 AI007641-06A2 to J.M.B), a Pilot/Feasibility grant from the UCSF Liver Center (P30 DK026743 to J.M.M.), NIH/NCRR UCSF - CTSI Grant Number UL1 RR024131, a grant to the UCSF - GIVI Center for AIDS Research (P30 AI027763), and the Harvey V. Berneking Living Trust. J.M.M. is a recipient of the NIH Director's Pioneer Award Program, part of the NIH Roadmap for Medical Research, through grant DPI OD00329.
The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
The information in this manuscript has not been presented previously at any meeting.
Source
203, 2
Pp. 196-206.
Jennifer M. Babik 1,2, Deborah Cohan 3, Alexander Monto 4, Dennis J. Hartigan-O'Connor 1 and Joseph M. McCune 1
+ Author Affiliations
1 Division of Experimental Medicine
2 Division of Infectious Diseases, Department of Medicine, University of California, San Francisco
3 Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco and San Francisco General Hospital
4 Division of Gastroenterology, Department of Medicine, University of California, San Francisco and the San Francisco Veterans Affairs Medical Center, San Francisco, California
Reprints or correspondence: Dr Joseph M. McCune, Division of Experimental Medicine, Department of Medicine, Box 1234, University of California, San Francisco, San Francisco, CA 94143-1234 (mike.mccune@ucsf.edu).
Abstract
Background. Although the rate of mother-to-child transmission of hepatitis C virus (HCV) is low, the effect of HCV exposure in utero on the fetal immune system is unknown.
Methods. Umbilical cord blood was obtained from 7 neonates born to HCV-seropositive, HCV RNA-positive women and 8 neonates born to HCV-seronegative women. Cord blood mononuclear cells were analyzed by immunophenotyping and by intracellular cytokine staining after HCV-specific and polyclonal stimulation. Plasma was analyzed for anti-HCV immunoglobulin M (IgM), cytokine/granzyme concentrations, and indoleamine 2,3-dioxygenase (IDO) activity.
Results. HCV-exposed neonates had significantly lower levels of regulatory T cells expressing HLA-DR, lower CD4+ and CD8+ T cell activation, and lower plasma levels of pro-inflammatory markers than did controls. However, CD4+ and CD8+ T cells from HCV-exposed neonates had higher IFN-γ production in response to polyclonal stimulation than did T cells from controls. IDO activity was similar between groups. No HCV-specific T cell responses or anti-HCV IgM were detected in any neonates.
Conclusions. HCV-exposed neonates showed a relative suppression of immune activation and pro-inflammatory markers, which was counterbalanced by an increased production capacity for IFN-γ. These results suggest that HCV encounters the fetal immune system in utero, and alters the balance between suppressive and pro-inflammatory responses.
Footnotes
Potential conflicts of interest: none reported.
Financial support: This work was supported in part by a Ruth L. Kirschstein National Research Service Award (T32 AI007641-06A2 to J.M.B), a Pilot/Feasibility grant from the UCSF Liver Center (P30 DK026743 to J.M.M.), NIH/NCRR UCSF - CTSI Grant Number UL1 RR024131, a grant to the UCSF - GIVI Center for AIDS Research (P30 AI027763), and the Harvey V. Berneking Living Trust. J.M.M. is a recipient of the NIH Director's Pioneer Award Program, part of the NIH Roadmap for Medical Research, through grant DPI OD00329.
The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
The information in this manuscript has not been presented previously at any meeting.
Source
Ocera Therapeutics Completes First in Human Studies with OCR-002 for the Treatment of Hyperammonemia and Hepatic Encephalopathy
Ocera has received Fast Track Designation and Orphan Drug Status and plans to initiate Phase 2 studies with OCR-002 in 2011.
SAN DIEGO, Dec. 15, 2010 /PRNewswire/ -- Ocera Therapeutics, Inc. announced today that it has completed two studies evaluating the safety and pharmacokinetics of OCR-002 (ornithine phenylacetate) which includes healthy volunteers and patients with liver cirrhosis. OCR-002 recently received Orphan Drug status and Fast Track designation by the United States Food and Drug Administration for the treatment of hyperammonemia (excessive ammonia levels) and resultant Hepatic encephalopathy. Patients with liver failure and decompensated cirrhosis may present with confusion and coma, a frequent complication known as acute hepatic encephalopathy (AHE) and an indicator of poor long-term survival.
Orphan Drug designation applies to a compound being developed to treat a rare medical condition. It offers a number of potential incentives, which may include a seven-year period of U.S. marketing exclusivity from the date of marketing authorization, funding for clinical studies, study design assistance, waiver of FDA user fees, and tax credits for clinical research. The Fast Track program is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions, and that demonstrate the potential to address unmet medical needs. Fast Track designated drugs often qualify for priority review, thereby expediting the FDA review process.
"Unlike current treatments that target the production of ammonia in the intestinal tract, OCR-002 directly reduces toxic levels of ammonia in the blood that lead to severe neurologic complications including coma. AHE is associated with substantial morbidity and mortality, and OCR-002 has the potential to be a novel therapeutic option for these patients," stated Dr. Laurent Fischer, CEO of Ocera Therapeutics. "Our receipt of Orphan Drug status and Fast Track designation for OCR-002 reinforce the clinical unmet need in AHE, and demonstrate the importance being placed on accelerating the development of drugs like this in order to reach the patients in need as quickly as possible." Ocera plans to initiate Phase 2 studies in 2011.
OCR-002 data presented at EASL, AASLD, and ISHEN in 2010 have confirmed that OCR-002 can consistently lower ammonia in multiple preclinical models of cirrhosis and acute liver failure and has been correlated with normalization of intracranial pressure, brain edema and neurologic function.
"OCR-002 is a promising new therapy for the acute care of patients with hyperammonemia and hepatic encephalopathy, a patient population for whom treatment options are currently very limited," stated Dr. Tarek Hassanein, Professor of Medicine and Director of Southern California Liver Centers, Coronado, CA.
About OCR-002
OCR-002 (ornithine phenylacetate) is a novel injectable treatment with a unique mechanism of action that directly reduces toxic levels of ammonia in the blood. When the liver is unable to detoxify ammonia, patients are at risk of developing hepatic encephalopathy, a condition that can lead to coma and death, requiring hospitalization that cost the U.S. healthcare system $1.2 billion every year. The compound has demonstrated in several published studies that it has a rapid and sustained effect in lowering toxic ammonia levels and can prevent severe neurologic complications in animal models of acute liver failure and liver cirrhosis. Ocera Therapeutics licensed OCR-002 from University College of London in December 2008.
About Hepatic Encephalopathy
Hepatic Encephalopathy (HE) is caused by the accumulation of toxic substances in the bloodstream, including ammonia, that are normally removed by the liver. HE ranges in severity from disorientation to confusion, coma and even death. With severe liver impairment, toxic substances such as ammonia accumulate in the blood and impair the function of brain cells. In acute liver failure, hyperammonemia can lead to cerebral hypertension, which can cause brain edema and death and may require a liver transplant.
About Ocera Therapeutics, Inc.
Ocera Therapeutics, based in San Diego, California, USA, is a privately held biopharmaceutical company focused on the development and commercialization of proprietary compounds to treat liver diseases and gastrointestinal disorders. Ocera has raised $62.5 million dollars in venture financing from Domain Associates, Sofinnova Ventures, Thomas, McNerney & Partners, Greenspring Associates and InterWest Partners. Additional information on the company can be found at http://www.oceratherapeutics.com/.
SOURCE Ocera Therapeutics, Inc.
RELATED LINKS
http://www.oceratherapeutics.com/
Source
SAN DIEGO, Dec. 15, 2010 /PRNewswire/ -- Ocera Therapeutics, Inc. announced today that it has completed two studies evaluating the safety and pharmacokinetics of OCR-002 (ornithine phenylacetate) which includes healthy volunteers and patients with liver cirrhosis. OCR-002 recently received Orphan Drug status and Fast Track designation by the United States Food and Drug Administration for the treatment of hyperammonemia (excessive ammonia levels) and resultant Hepatic encephalopathy. Patients with liver failure and decompensated cirrhosis may present with confusion and coma, a frequent complication known as acute hepatic encephalopathy (AHE) and an indicator of poor long-term survival.
Orphan Drug designation applies to a compound being developed to treat a rare medical condition. It offers a number of potential incentives, which may include a seven-year period of U.S. marketing exclusivity from the date of marketing authorization, funding for clinical studies, study design assistance, waiver of FDA user fees, and tax credits for clinical research. The Fast Track program is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions, and that demonstrate the potential to address unmet medical needs. Fast Track designated drugs often qualify for priority review, thereby expediting the FDA review process.
"Unlike current treatments that target the production of ammonia in the intestinal tract, OCR-002 directly reduces toxic levels of ammonia in the blood that lead to severe neurologic complications including coma. AHE is associated with substantial morbidity and mortality, and OCR-002 has the potential to be a novel therapeutic option for these patients," stated Dr. Laurent Fischer, CEO of Ocera Therapeutics. "Our receipt of Orphan Drug status and Fast Track designation for OCR-002 reinforce the clinical unmet need in AHE, and demonstrate the importance being placed on accelerating the development of drugs like this in order to reach the patients in need as quickly as possible." Ocera plans to initiate Phase 2 studies in 2011.
OCR-002 data presented at EASL, AASLD, and ISHEN in 2010 have confirmed that OCR-002 can consistently lower ammonia in multiple preclinical models of cirrhosis and acute liver failure and has been correlated with normalization of intracranial pressure, brain edema and neurologic function.
"OCR-002 is a promising new therapy for the acute care of patients with hyperammonemia and hepatic encephalopathy, a patient population for whom treatment options are currently very limited," stated Dr. Tarek Hassanein, Professor of Medicine and Director of Southern California Liver Centers, Coronado, CA.
About OCR-002
OCR-002 (ornithine phenylacetate) is a novel injectable treatment with a unique mechanism of action that directly reduces toxic levels of ammonia in the blood. When the liver is unable to detoxify ammonia, patients are at risk of developing hepatic encephalopathy, a condition that can lead to coma and death, requiring hospitalization that cost the U.S. healthcare system $1.2 billion every year. The compound has demonstrated in several published studies that it has a rapid and sustained effect in lowering toxic ammonia levels and can prevent severe neurologic complications in animal models of acute liver failure and liver cirrhosis. Ocera Therapeutics licensed OCR-002 from University College of London in December 2008.
About Hepatic Encephalopathy
Hepatic Encephalopathy (HE) is caused by the accumulation of toxic substances in the bloodstream, including ammonia, that are normally removed by the liver. HE ranges in severity from disorientation to confusion, coma and even death. With severe liver impairment, toxic substances such as ammonia accumulate in the blood and impair the function of brain cells. In acute liver failure, hyperammonemia can lead to cerebral hypertension, which can cause brain edema and death and may require a liver transplant.
About Ocera Therapeutics, Inc.
Ocera Therapeutics, based in San Diego, California, USA, is a privately held biopharmaceutical company focused on the development and commercialization of proprietary compounds to treat liver diseases and gastrointestinal disorders. Ocera has raised $62.5 million dollars in venture financing from Domain Associates, Sofinnova Ventures, Thomas, McNerney & Partners, Greenspring Associates and InterWest Partners. Additional information on the company can be found at http://www.oceratherapeutics.com/.
SOURCE Ocera Therapeutics, Inc.
RELATED LINKS
http://www.oceratherapeutics.com/
Source
Subscribe to:
Posts (Atom)