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.
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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
December 15, 2010
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
December 14, 2010
Pharmasset Initiates Exploratory Interferon Sparing Clinical Trial of PSI-7977 for Chronic Hepatitis C
Exploratory phase 2 trial in patients with HCV genotype 2 or 3 to receive PSI-7977 400mg QD and ribavirin, with 0-12 weeks of pegylated interferon
Interim data expected in first half of 2011
PRINCETON, N.J., Dec. 14, 2010 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today that dosing has begun in an exploratory study of PSI-7977, a nucleotide analog polymerase inhibitor, for the treatment of chronic hepatitis C (HCV). The trial will evaluate PSI-7977 400mg QD in combination with ribavirin (RBV), with 0, 4, 8, or 12 weeks of pegylated interferon alfa 2a (Peg-IFN) in treatment-naive patients infected with HCV genotype 2 or 3.
"Based on the encouraging efficacy, safety and resistance data from the Phase 2a trial with PSI-7977 in combination with pegylated interferon and ribavirin, we initiated a study to explore shorter durations of interferon, including an interferon-free regimen in treatment naïve patients with HCV genotype 2 or 3," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "An important limitation to the current treatment of HCV patients is the use of interferon with its associated side effect profile. We believe that PSI-7977's high barrier to resistance and the lack of a significant effect of IL28B genotype in the Phase 2a trial provide us an opportunity with PSI-7977 to explore shorter durations of interferon, and potentially even removing it from the treatment regimen altogether."
About the Trial
The trial is anticipated to enroll approximately 40 patients infected with HCV genotype 2 or 3 who have not previously been treated. The primary endpoint of the trial will be the assessment of safety and tolerability of PSI-7977 400mg QD and RBV for 12 weeks, administered with or without pegylated interferon (Peg-IFN) in treatment naïve patients with HCV genotypes 2 or 3. The trial will be conducted in New Zealand. Patients will be randomized into one of 4 arms:
-- PSI-7977 400mg QD in combination with RBV for 12 weeks (no interferon);
-- PSI-7977 400mg QD in combination with RBV for 12 weeks, with only 4 weeks of Peg-IFN;
-- PSI-7977 400mg QD in combination with RBV for 12 weeks, with only 8 weeks of Peg-IFN;
-- PSI-7977 400mg QD in combination with Peg-IFN and RBV for 12 weeks.
Patients will be stratified by HCV genotype and IL28B status to ensure balance across cohorts.
Pharmasset anticipates reporting interim data from this trial in the first half of 2011.
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have four clinical-stage product candidates. RG7128, a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys(R) plus Copegus(R) and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys(R) and Copegus(R) to treat chronic HCV. These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage HCV candidates include PSI-7977, an unpartnered uracil nucleotide analog that has recently initiated dosing in a Phase 2b study in patients with HCV genotypes 1, 2, or 3, and PSI-938, an unpartnered guanosine nucleotide analog which recently completed a 7-day monotherapy study. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development.
Pegasys(R) and Copegus(R) are registered trademarks of Roche.
Forward-Looking Statements
Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are "forward-looking statements," that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2010 filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.
Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Office +1 (609) 613-4181
SOURCE Pharmasset, Inc.
RELATED LINKS
http://www.pharmasset.com/
Source
Interim data expected in first half of 2011
PRINCETON, N.J., Dec. 14, 2010 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today that dosing has begun in an exploratory study of PSI-7977, a nucleotide analog polymerase inhibitor, for the treatment of chronic hepatitis C (HCV). The trial will evaluate PSI-7977 400mg QD in combination with ribavirin (RBV), with 0, 4, 8, or 12 weeks of pegylated interferon alfa 2a (Peg-IFN) in treatment-naive patients infected with HCV genotype 2 or 3.
"Based on the encouraging efficacy, safety and resistance data from the Phase 2a trial with PSI-7977 in combination with pegylated interferon and ribavirin, we initiated a study to explore shorter durations of interferon, including an interferon-free regimen in treatment naïve patients with HCV genotype 2 or 3," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "An important limitation to the current treatment of HCV patients is the use of interferon with its associated side effect profile. We believe that PSI-7977's high barrier to resistance and the lack of a significant effect of IL28B genotype in the Phase 2a trial provide us an opportunity with PSI-7977 to explore shorter durations of interferon, and potentially even removing it from the treatment regimen altogether."
About the Trial
The trial is anticipated to enroll approximately 40 patients infected with HCV genotype 2 or 3 who have not previously been treated. The primary endpoint of the trial will be the assessment of safety and tolerability of PSI-7977 400mg QD and RBV for 12 weeks, administered with or without pegylated interferon (Peg-IFN) in treatment naïve patients with HCV genotypes 2 or 3. The trial will be conducted in New Zealand. Patients will be randomized into one of 4 arms:
-- PSI-7977 400mg QD in combination with RBV for 12 weeks (no interferon);
-- PSI-7977 400mg QD in combination with RBV for 12 weeks, with only 4 weeks of Peg-IFN;
-- PSI-7977 400mg QD in combination with RBV for 12 weeks, with only 8 weeks of Peg-IFN;
-- PSI-7977 400mg QD in combination with Peg-IFN and RBV for 12 weeks.
Patients will be stratified by HCV genotype and IL28B status to ensure balance across cohorts.
Pharmasset anticipates reporting interim data from this trial in the first half of 2011.
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have four clinical-stage product candidates. RG7128, a cytosine nucleoside analog for chronic HCV infection, is in two Phase 2b clinical studies in combination with Pegasys(R) plus Copegus(R) and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys(R) and Copegus(R) to treat chronic HCV. These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage HCV candidates include PSI-7977, an unpartnered uracil nucleotide analog that has recently initiated dosing in a Phase 2b study in patients with HCV genotypes 1, 2, or 3, and PSI-938, an unpartnered guanosine nucleotide analog which recently completed a 7-day monotherapy study. We also have in our pipeline an additional purine nucleotide analog, PSI-661, in advanced preclinical development.
Pegasys(R) and Copegus(R) are registered trademarks of Roche.
Forward-Looking Statements
Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release that are not historical facts are "forward-looking statements," that involve risks, uncertainties, and other important factors, including, without limitation, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of risks, uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our Annual Report on Form 10-K for the fiscal year ended September 30, 2010 filed with the Securities and Exchange Commission and discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission.
Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Office +1 (609) 613-4181
SOURCE Pharmasset, Inc.
RELATED LINKS
http://www.pharmasset.com/
Source
Steatosis, Obesity, Peg-IFN Dose Reduction & Menopause are Associated with Relapse in Chronic Hepatitis C Patients Treated with Pegylated Interferon Plus Ribavirin
Reported by Jules Levin, AASLD Nov 2 2010
C. Stern1; M. Martinot-Peignoux1; M. Ripault1; N. Boyer1; A. Cardoso1; A. El Ray1; T. Asselah1; D. Valla1; P. Marcellin1 1. Service d'Hepatologie, Hôpital Beaujon, Clichy, France.
BACKGROUND/AIMS: Relapse after treatment of chronic hepatitis C (CHC) patients with the combination of pegylated interferon (PEG-IFN)-α and ribavirin (RBV) is observed in 30% of patients with end of therapy (EOT) response. Factors associated with relapse are not well known. The aim of this study was to evaluate the factors related to relapse in CHC patients, particularly in female patients, treated with PEG-IFN in combination with RBV.
METHODS: A total of 249 consecutive naive CHC patients treated with PEG-IFN-α-2a or -2b plus RBV (800 to 1200 mg/day) and with EOT response were included. Among these, 84 (34%) patients were female. Duration of therapy was defined according to the current guidelines. Clinical, biological, virological and histological data were collected. Type of PEG-IFN, initial doses and modifications of therapy were analyzed. The efficacy of treatment was evaluated with a sensitive qualitative HCV RNA assay (<15 IU/mL). Factors associated with relapse were analyzed.
RESULTS: Relapse was observed in 34% of patients; 50% received PEG-IFN-α2a. Overall population presented the following characteristics: mean age 47±11, obesity (BMI ≥30) in 10%, genotype 1 in 33%, advanced fibrosis (≥F3) in 24% and marked steatosis (≥30%) in 27%.
In the logistic regression, factors related to relapse in overall population were: obesity (p=0.011), genotype 1 (p=0.001), marked steatosis (p=0.006) and PEG-IFN dose reduction (p<0.001). In female patients, menopause was observed in 59% (mean age 48±6). Therefore, to confirm a possible impact of menopause on relapse in CHC female patients, we compared patients under and older than 50 years according to gender. In males (n=165), relapse was present in 22% and 28% of patients under 50 years and older than 50 years (p=0.38), respectively. When relapse rates were analyzed in females (n=84), a statistically difference related to age was observed (14% vs 37%, p=0.023). Among female patients, factors associated with relapse were: menopause (p=0.006), obesity (p=0.031), high viral load (≥400,000 IU/mL) (p=0.014), genotype 1 (p=0.034) and necro-inflammatory activity ≥A2 (p=0.043). In the logistic regression, only menopause was independently associated with relapse in CHC female patients (p=0.007, 95% CI 1.66 - 24.47).
CONCLUSION: CHC patients infected with genotype 1 and presenting obesity and marked steatosis have higher rates of relapse. PEG-IFN reduction, but not ribavirin reduction, is associated with relapse. In female patients, menopause has a negative impact on SVR rates.
Source
C. Stern1; M. Martinot-Peignoux1; M. Ripault1; N. Boyer1; A. Cardoso1; A. El Ray1; T. Asselah1; D. Valla1; P. Marcellin1 1. Service d'Hepatologie, Hôpital Beaujon, Clichy, France.
BACKGROUND/AIMS: Relapse after treatment of chronic hepatitis C (CHC) patients with the combination of pegylated interferon (PEG-IFN)-α and ribavirin (RBV) is observed in 30% of patients with end of therapy (EOT) response. Factors associated with relapse are not well known. The aim of this study was to evaluate the factors related to relapse in CHC patients, particularly in female patients, treated with PEG-IFN in combination with RBV.
METHODS: A total of 249 consecutive naive CHC patients treated with PEG-IFN-α-2a or -2b plus RBV (800 to 1200 mg/day) and with EOT response were included. Among these, 84 (34%) patients were female. Duration of therapy was defined according to the current guidelines. Clinical, biological, virological and histological data were collected. Type of PEG-IFN, initial doses and modifications of therapy were analyzed. The efficacy of treatment was evaluated with a sensitive qualitative HCV RNA assay (<15 IU/mL). Factors associated with relapse were analyzed.
RESULTS: Relapse was observed in 34% of patients; 50% received PEG-IFN-α2a. Overall population presented the following characteristics: mean age 47±11, obesity (BMI ≥30) in 10%, genotype 1 in 33%, advanced fibrosis (≥F3) in 24% and marked steatosis (≥30%) in 27%.
In the logistic regression, factors related to relapse in overall population were: obesity (p=0.011), genotype 1 (p=0.001), marked steatosis (p=0.006) and PEG-IFN dose reduction (p<0.001). In female patients, menopause was observed in 59% (mean age 48±6). Therefore, to confirm a possible impact of menopause on relapse in CHC female patients, we compared patients under and older than 50 years according to gender. In males (n=165), relapse was present in 22% and 28% of patients under 50 years and older than 50 years (p=0.38), respectively. When relapse rates were analyzed in females (n=84), a statistically difference related to age was observed (14% vs 37%, p=0.023). Among female patients, factors associated with relapse were: menopause (p=0.006), obesity (p=0.031), high viral load (≥400,000 IU/mL) (p=0.014), genotype 1 (p=0.034) and necro-inflammatory activity ≥A2 (p=0.043). In the logistic regression, only menopause was independently associated with relapse in CHC female patients (p=0.007, 95% CI 1.66 - 24.47).
CONCLUSION: CHC patients infected with genotype 1 and presenting obesity and marked steatosis have higher rates of relapse. PEG-IFN reduction, but not ribavirin reduction, is associated with relapse. In female patients, menopause has a negative impact on SVR rates.
Source
IL-28B Genotype is a Major Determinant of the Induction of a Virological Response by High-Dose Peginterferon and Ribavirin in Null-responders to SOC Therapy: Pegasys double-dose significantly increased early virologic response
Reported by Jules Levin
AASLD Nov 2 2010 Boston
NATAP
Stephane Chevaliez1,2, Christophe Hezode1,3, Alexandre Soulier1,2, Bruno Costes2,4, Magali Bouvier-Alias1,2, Stephanie Rouanet5, Juliette Foucher6, Jean-Pierre Bronowicki7, Albert Tran8, Isabelle Rosa9, Philippe Mathurin10, Laurent Alric11, Vincent Leroy12, Victor De Ledinghen6, Ariane Mallat1,3, Mariem Charaf-Eddine5, Gerard Babany5, and Jean-Michel Pawlotsky1,2
1National Reference Center for Viral Hepatitis B, C and delta, Virology, Hôpital Henri Mondor, Creteil, France; 2INSERM U955, Creteil, France; 3Hepatology and Gastroenterology, Hôpital Henri Mondor, Creteil, France; 4 Biochemistry, Hôpital Henri Mondor, Creteil, France; 5Roche, Neuilly-Seine, France; 6Hepatology and Gastroenterology, Hôpital Haut-Levêque, Pessac, France; 7Hepatology and Gastroenterology, Hôpital de Brabois, Nancy, France; 8Hepatology and Gastroenterology, Hôpital de l'Archet, Nice, France; 9Hepatology and Gastroenterology, Centre Hospitalier Intercommunal, Creteil, France; 10Hepatology and Gastroenterology, Hôpital Claude Huriez, Lille, France; 11Internal Medicine, Hôpital Purpan, Toulouse, France; 12Hepatology and Gastroenterology, Hôpital de la Tronche, Grenoble, France
from Jules: we need to wait for the IL28B subanalyses from the telaprevir ADVANCE & boceprevir SPRINT2 studies in order to see how to use this information. Using double dose Pegasys in this study appeared to on average increase the virologic response quite a lot by weeks 4, 8 and 12 compared to prior use of the standard Pegasys dose for both TT and CT genotypes. CT genotype achieved better virologic response than TT genotype in this study, by week 24: 44% of TT and 70% of CT achieved >2 log viral load reduction. These data suggest that double-dose Pegasys 360 ug/week in combination with telaprevir or boceprevir may significantly increase virologic response and SVR. Conceivably, double-dose Pegasys during a lead-in and during therapy with telaprevir or boceprevir could increase SVR rates potentially quite a lot based on these data. There is a suggestion that an HCV protease resenesitizes the patient's internal interferon response so let's see how the TTs and CTs respond in the subanalyses from Advance & Sprint.
ABSTRACT:
Polymorphisms upstream of the region encoding IL28B have been shown to be associated with both natural and treatment-induced control of HCV infection. With new therapies using direct acting antiviral molecules, a null response to IFN is associated with treatment failure and selection of resistant viruses. Our goal was to assess, in null-responders to IFN-ribavirin therapy, whether the IL28B genotype has an influence and predictive value on the ability of high-dose pegylated IFN and ribavirin retreatment to induce a virological response.
METHODS:
83 genotype 1 null-responders received peg-IFN alpha-2a, 360 µg/week in one or two injections, plus ribavirin, 1000-1200 or 1200-1600 mg/d. Genotyping of the IL28B SNP rs12979860 was performed from host cell DNA by means of a real-time PCR method using minor groove binding probes. RESULTS: The IL28B genotype was determined in all 83 patients: 3 (3.6%) had a CC genotype and were removed to allow comparison between CT (n=55) and TT (n=25) patients. The difference between reductions in HCV RNA levels between TT and CT patients was significant at week 2 (<0.5 vs ≥0.5 Log, p=0.02), at week 4 (<1 vs ≥1 Log, p=0.008), and at weeks 12 and 24 (<2 vs ≥2 Log p=0.02). When comparing CT and TT patients, the odds ratio were 3.09 for a more than 0.5 Log drop at week 2; 3.86 for a more than 1 Log drop at week 4; 3.08 for a more than 2 Log drop at week 12; 3.10 for a more than 2 Log drop at week 24; and 3.57 for an undetectable HCV RNA at week 24.
CONCLUSIONS:
Most patients who fail to respond to pegylated IFN and ribavirin carry either TT or CT rs12979860 genotypes. CT patients are significantly more likely to respond to higher doses of IFN and the difference is significant at week 2. This indicates that the IL28B genotype is a marker of host cell responsiveness to IFN. These findings will have major implications in the treatment of HCV infection with higher peg-IFN doses in combination with ribavirin and direct acting antivirals.
Continue Reading ...
AASLD Nov 2 2010 Boston
NATAP
Stephane Chevaliez1,2, Christophe Hezode1,3, Alexandre Soulier1,2, Bruno Costes2,4, Magali Bouvier-Alias1,2, Stephanie Rouanet5, Juliette Foucher6, Jean-Pierre Bronowicki7, Albert Tran8, Isabelle Rosa9, Philippe Mathurin10, Laurent Alric11, Vincent Leroy12, Victor De Ledinghen6, Ariane Mallat1,3, Mariem Charaf-Eddine5, Gerard Babany5, and Jean-Michel Pawlotsky1,2
1National Reference Center for Viral Hepatitis B, C and delta, Virology, Hôpital Henri Mondor, Creteil, France; 2INSERM U955, Creteil, France; 3Hepatology and Gastroenterology, Hôpital Henri Mondor, Creteil, France; 4 Biochemistry, Hôpital Henri Mondor, Creteil, France; 5Roche, Neuilly-Seine, France; 6Hepatology and Gastroenterology, Hôpital Haut-Levêque, Pessac, France; 7Hepatology and Gastroenterology, Hôpital de Brabois, Nancy, France; 8Hepatology and Gastroenterology, Hôpital de l'Archet, Nice, France; 9Hepatology and Gastroenterology, Centre Hospitalier Intercommunal, Creteil, France; 10Hepatology and Gastroenterology, Hôpital Claude Huriez, Lille, France; 11Internal Medicine, Hôpital Purpan, Toulouse, France; 12Hepatology and Gastroenterology, Hôpital de la Tronche, Grenoble, France
from Jules: we need to wait for the IL28B subanalyses from the telaprevir ADVANCE & boceprevir SPRINT2 studies in order to see how to use this information. Using double dose Pegasys in this study appeared to on average increase the virologic response quite a lot by weeks 4, 8 and 12 compared to prior use of the standard Pegasys dose for both TT and CT genotypes. CT genotype achieved better virologic response than TT genotype in this study, by week 24: 44% of TT and 70% of CT achieved >2 log viral load reduction. These data suggest that double-dose Pegasys 360 ug/week in combination with telaprevir or boceprevir may significantly increase virologic response and SVR. Conceivably, double-dose Pegasys during a lead-in and during therapy with telaprevir or boceprevir could increase SVR rates potentially quite a lot based on these data. There is a suggestion that an HCV protease resenesitizes the patient's internal interferon response so let's see how the TTs and CTs respond in the subanalyses from Advance & Sprint.
ABSTRACT:
Polymorphisms upstream of the region encoding IL28B have been shown to be associated with both natural and treatment-induced control of HCV infection. With new therapies using direct acting antiviral molecules, a null response to IFN is associated with treatment failure and selection of resistant viruses. Our goal was to assess, in null-responders to IFN-ribavirin therapy, whether the IL28B genotype has an influence and predictive value on the ability of high-dose pegylated IFN and ribavirin retreatment to induce a virological response.
METHODS:
83 genotype 1 null-responders received peg-IFN alpha-2a, 360 µg/week in one or two injections, plus ribavirin, 1000-1200 or 1200-1600 mg/d. Genotyping of the IL28B SNP rs12979860 was performed from host cell DNA by means of a real-time PCR method using minor groove binding probes. RESULTS: The IL28B genotype was determined in all 83 patients: 3 (3.6%) had a CC genotype and were removed to allow comparison between CT (n=55) and TT (n=25) patients. The difference between reductions in HCV RNA levels between TT and CT patients was significant at week 2 (<0.5 vs ≥0.5 Log, p=0.02), at week 4 (<1 vs ≥1 Log, p=0.008), and at weeks 12 and 24 (<2 vs ≥2 Log p=0.02). When comparing CT and TT patients, the odds ratio were 3.09 for a more than 0.5 Log drop at week 2; 3.86 for a more than 1 Log drop at week 4; 3.08 for a more than 2 Log drop at week 12; 3.10 for a more than 2 Log drop at week 24; and 3.57 for an undetectable HCV RNA at week 24.
CONCLUSIONS:
Most patients who fail to respond to pegylated IFN and ribavirin carry either TT or CT rs12979860 genotypes. CT patients are significantly more likely to respond to higher doses of IFN and the difference is significant at week 2. This indicates that the IL28B genotype is a marker of host cell responsiveness to IFN. These findings will have major implications in the treatment of HCV infection with higher peg-IFN doses in combination with ribavirin and direct acting antivirals.
Continue Reading ...
Doctors Claim HIV-Positive Man Cured by Stem Cell Transplant
Published December 14, 2010
FoxNews.com
There’s an estimated 33 million people worldwide living with HIV/AIDS, and now doctors believe one of them may have been cured of the virus after receiving a stem cell transplant in 2007, the medical journal Blood reported.
Timothy Ray Brown, an HIV-positive American living in Germany, had leukemia and was undergoing chemotherapy, when he received a transplant of stem cells from a donor carrying a rare, inherited gene mutation that seems to make carriers virtually immune to HIV infection.
The transplant appeared to wipe out both diseases, giving hope to doctors, but Dr. Anthony Fauci, director of the National Institutes of Allergy and Infectious Diseases, who has been studying HIV/AIDS for almost 30 years, said while this is an interesting proof of concept, it’s absurdly impractical.
“It’s hard enough to get a good compatible match for a transplant like this,” Fauci told FoxNews.com, “But you also have to find compatible donor that has this genetic defect, and this defect is only found in 1 percent of the Caucasian population and zero percent of the black population. This is very rare.”
Fauci said while this patient is “functionally cured” this is not something you can do with every HIV-infected individual.
“This is not prime time to me at all,” he said. “This is a very unusual situation that has little practical application for a simple reason. This donor not only had to be a good compatible match, but the donor had to have a genetic defect of cells that do not express the receptor that the HIV virus needs to enter the cell.”
Fauci also pointed to the fact that this transplant process is not only expensive, it’s incredibly painful and complicated, and requires the patient to start a whole new regimen of drugs.
“This patient is trading one poison for another. He may not have to be on antiretroviral drugs anymore, but he has to take immunosuppressant drugs now to prevent the rejection of his transplant cells. Again, what this is, is an interesting proof of concept, but it’s absolutely impractical.”
Dr. Thomas Quinn, director of Johns Hopkins Center for Global Health told FoxNews.com that he is very familiar with the “Berlin patient” case.
“This was a new report that looked much deeper into whether HIV could still be present or lurking in the body in some way, not cured, and since the transplant he remains viral free and his cells appear to be resistant to infection,” he said.
Quinn said he agrees with the researchers on this case that it would be qualified as the first HIV cure, opening the door to alternative means of curing HIV.
“He [Brown] has been without therapy for three years and appears to be free of the virus,” he said. “It gives hope to the millions of people infected with HIV that cure is a feasible option in the future.”
Even though Brown’s procedure proved to be successful, Quinn also warns that this was a rare case and a bone marrow transplant is not a cure-all for other HIV patients.
“It is a near fatal procedure that he had to have done because of the leukemia, but this procedure is very expensive and you have to be transplanted with a donor who is shown to be already resistant to HIV,” Quinn said. “You’re asking for a tall order to replicate this in the future.”
Brown’s case was published in a February 2009 issue of the New England Journal of Medicine.
Click here to read more from the journal Blood (subscription is required).
Source
FoxNews.com
There’s an estimated 33 million people worldwide living with HIV/AIDS, and now doctors believe one of them may have been cured of the virus after receiving a stem cell transplant in 2007, the medical journal Blood reported.
Timothy Ray Brown, an HIV-positive American living in Germany, had leukemia and was undergoing chemotherapy, when he received a transplant of stem cells from a donor carrying a rare, inherited gene mutation that seems to make carriers virtually immune to HIV infection.
The transplant appeared to wipe out both diseases, giving hope to doctors, but Dr. Anthony Fauci, director of the National Institutes of Allergy and Infectious Diseases, who has been studying HIV/AIDS for almost 30 years, said while this is an interesting proof of concept, it’s absurdly impractical.
“It’s hard enough to get a good compatible match for a transplant like this,” Fauci told FoxNews.com, “But you also have to find compatible donor that has this genetic defect, and this defect is only found in 1 percent of the Caucasian population and zero percent of the black population. This is very rare.”
Fauci said while this patient is “functionally cured” this is not something you can do with every HIV-infected individual.
“This is not prime time to me at all,” he said. “This is a very unusual situation that has little practical application for a simple reason. This donor not only had to be a good compatible match, but the donor had to have a genetic defect of cells that do not express the receptor that the HIV virus needs to enter the cell.”
Fauci also pointed to the fact that this transplant process is not only expensive, it’s incredibly painful and complicated, and requires the patient to start a whole new regimen of drugs.
“This patient is trading one poison for another. He may not have to be on antiretroviral drugs anymore, but he has to take immunosuppressant drugs now to prevent the rejection of his transplant cells. Again, what this is, is an interesting proof of concept, but it’s absolutely impractical.”
Dr. Thomas Quinn, director of Johns Hopkins Center for Global Health told FoxNews.com that he is very familiar with the “Berlin patient” case.
“This was a new report that looked much deeper into whether HIV could still be present or lurking in the body in some way, not cured, and since the transplant he remains viral free and his cells appear to be resistant to infection,” he said.
Quinn said he agrees with the researchers on this case that it would be qualified as the first HIV cure, opening the door to alternative means of curing HIV.
“He [Brown] has been without therapy for three years and appears to be free of the virus,” he said. “It gives hope to the millions of people infected with HIV that cure is a feasible option in the future.”
Even though Brown’s procedure proved to be successful, Quinn also warns that this was a rare case and a bone marrow transplant is not a cure-all for other HIV patients.
“It is a near fatal procedure that he had to have done because of the leukemia, but this procedure is very expensive and you have to be transplanted with a donor who is shown to be already resistant to HIV,” Quinn said. “You’re asking for a tall order to replicate this in the future.”
Brown’s case was published in a February 2009 issue of the New England Journal of Medicine.
Click here to read more from the journal Blood (subscription is required).
Source
Hepatitis Experts Create Roadmap for Accelerating the Development of Targeted Therapies for Hepatitis C Virus
WASHINGTON, Dec. 14, 2010 /PRNewswire-USNewswire/ -- To improve the care for individuals infected with the hepatitis C virus, a major health problem and a leading cause of chronic liver disease around the world, nearly 200 international hepatitis experts have taken an important step in escalating the introduction of a new class of targeted therapies for HCV – direct-acting antivirals (DAAs).
December 6 at a major scientific meeting – Advancing HCV Drug Development: A Collaborative Approach – convened by the Forum for Collaborative HIV Research, researchers, hepatitis advocates, members of industry and representatives from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) created the roadmap for accelerating the development of DAAs, agreeing that this new class of drugs targeting specific hepatitis C virus proteins has the same potential to improve treatment outcomes for people with HCV as antiretroviral drugs changed the standard of care in HIV. Currently, two DAA compounds have advanced into phase 3 development in the United State and EU, and many more are in phase 2 trials and likely to advance to phase 3 research in the near future.
"If there was ever a time when we can change the course of HCV, it is now," said Veronica Miller, Ph.D., Director of the Forum. "We are now where we were with HIV more than a decade ago and can apply many of the lessons learned from HIV drug development to significantly accelerate the progress in bringing new and better HCV therapies to market."
DAAs directly attack the ability of the hepatitis C virus to replicate and can increase the cure rate in certain HCV patients to between 60 and 70 percent– a major advance over the 40 percent success rate associated with the currently recommended treatment for chronic HCV infection, the combination of pegylated interferon and ribavirin. Although the first DAAs still require concomitant use with current HCV medications, these new compounds will shorten the length of time on pegylated interferon and ribavirin therapy, which hepatitis specialists noted is often difficult to tolerate and has significant adverse event profiles that limit treatment in many patients. According to the latest data, between 15 and 30 percent of HCV patients started on current HCV therapy are unable to complete the year of treatment now required because they cannot tolerate the side effects.
Charting the future of HCV drug development, the meeting participants applied FDA's new guidance on conducting clinical trials on DAAs, which was issued in September 2010 in draft form and expected to be finalized in 2011. According to Jeffrey S. Murray, M.D., M.P.H., Deputy Director of the Division of Antiviral Drug Products in FDA's Center for Drug Evaluation and Research, the draft guidance follows the same approach FDA uses in developing HIV and oncology drugs. For early clinical testing, FDA recognizes that most if not all DAAs for HCV will be used in combination with other approved drug and therefore, recommends studies examining the relationship between the new DAA agent and both pegylated interferon and ribavirin as well as testing the combination antiviral activity. FDA's draft guidance also calls for using the results from proof-in-concept trials (meaning a study in HCV infected patients that demonstrates initial activity as measured by reductions in the HCV viral load) to guide dose selection for subsequent Phase 2 trials in which DAAs are studied for longer durations as part of a combination regimen. FDA is further encouraging drug sponsors to design development plans for combinations of two or more DAAs.
"The good news for the HCV community is that more drugs are coming," said Jur Strobos, MD, JD, FACEP, Deputy Director of the Forum. "The bad news is we don't know how to combine them and that is what we need to study."
With FDA's guidance as the framework, the hepatitis experts also identified the major factors researchers must take into account when designing clinical trials for DAAs and other new HCV therapies. Among the major issues cited are the emergence of resistant virus and its potential management, and including in future DAA clinical trials those special populations with significant unmet needs in HCV therapy. These patients include individuals co-infected with HIV, liver transplant recipients, patients with decompensated cirrhosis, opioid users and those on opiate substitution therapy, and children. According to the Centers for Disease Control and Prevention (CDC), between 5 and 6 percent of infants born to HCV infected women contract the infection from their mothers and the majority of those infants will develop a chronic infection.
Focusing on the special needs of pediatric patients, leaders from both FDA and EMA agreed that the time to start investigating DAAs in children is when sufficient safety data exist in adults. As explained by specialists in pediatric liver disease, children with HCV often tolerate drug therapy better than adults, which is why the ideal age to start children in pediatric trials for DAAs is when they are 3 years old. According to hepatitis experts, the beneficial impact of a 'cure' for children, preferably before they start school, cannot be overestimated.
Reducing Disparities in HCV Clinical Trials
Because identifying potential differences among groups treated with a therapeutic regimen is an important goal of human studies, the HCV community singled out the under-representation of women, older people and different ethnic subgroups in clinical trials as the problem requiring immediate attention and change at a systemic level. Although there is a higher prevalence of HCV in men than women, women metabolize HCV drugs differently and are more affected by autoimmune diseases, which share similar symptoms with HCV. Women also are twice as likely as men to suffer from depression, which is a common side effect of treatment with HCV medications.
Even more challenging for the HCV community is increasing the representation of older HCV-infected adults in HCV clinical trials, even though Baby Boomers constitute the majority of hepatitis C infections in the United States and are often less responsive than younger generations to antiviral treatment. Compounding the problem, older HCV patients are more difficult to treat, due to the increased prevalence of co-morbid conditions, such as diabetes, dyslipidemia, and other metabolic conditions that are correlated to chronic liver disease. Aging is also strongly associated with liver fibrosis progression, which means older HCV patients are likely to have advanced liver disease and a high risk for impending liver complications. But despite this reality, few studies have examined the age-specific factors of chronic HCV infection and the clinical management of the infection in this patient population.
More than an issue of fairness, HCV experts associate better designed clinical research studies with the increased ability of scientists to catalog and understand the influence of genetic and non-genetic factors on individual and group responses to new treatments. Findings from the large amount of genetic data generated to date show that more than 90 percent of the observed genetic variations occur within, rather than between groups. This underscores the fact that gender and ethnicity have biomedical consequences when evaluating patients with more resistant virus and with more severe disease.
Designing the Research Roadmap to Address a Growing Public Health Threat
Accelerating the development of DAAs to improve HCV treatment outcomes is especially warranted now that the hepatitis C virus has become the most common chronic blood borne infection in the U.S. According to new government estimates, approximately 4.1 million Americans are infected with HCV, of whom 60 to 70 percent will develop chronic liver disease. Currently, almost half of all liver transplants in the U.S. are performed for end-stage hepatitis C. Moreover, because liver disease is one of the leading causes of death in the U.S., the CDC predicts that deaths from chronic liver disease attributed to hepatitis C will double or triple over the next 15 to 20 years.
To change these statistics, hepatitis specialists focused on ways to advance HCV drug development so DAAs and other new classes of drugs for HCV can reach the market quickly. Here, the experts reached agreement on a number of issues:
• Exposure to new single agents – because HCV remains sensitive to ribavirin and pegylated interferon, longer initial studies may be recommended to evaluate single drugs and novel combinations of drugs
• Composition of patients in early studies (phase 1 and 2a) – early studies should be large enough so results with one type of virus or one group of patients can be easily discerned. Focusing on specific genetic sub-populations will also ensure that early studies do not produce confusing results
• Drug resistance in HCV patients – unlike HIV, drug resistance in HCV may not be as large a concern because HCV does not integrate into host DNA as HIV does. Thus, resistant strains are not archived and there is the potential that resistant patients can be retreated with different combinations regimens, as and when they become available
• Baseline parameters – there is the need to develop predictive algorithms based on baseline characteristics such as gender, body weight, HCV genotypes and subtypes
• Exclusion of former and current drug users in clinical trials – exclusion is unnecessary and does not serve the field well. Over 60 percent of patients with HCV are infected through drug use, indicating the need to have quality data to guide treatment decisions in this patient population
As a next step, the Forum for Collaborative HIV Research will publish the consensus of this scientific meeting to advance the research agenda. Once published, the report will be distributed widely to the Forum's many constituencies – government, industry, patient advocates, healthcare providers, foundations, health insurers and academia – with the goal of advancing research on HCV and driving public policy.
About the Forum for Collaborative HIV Research
Now part of the University of California (UC), Berkeley School of Public Health and based in Washington, DC, the Forum was founded in 1997 as the outgrowth of a White House initiative which called for an ongoing collaboration among stakeholders to address emerging issues in HIV/AIDS and set the research strategy. Representing government, industry, patient advocates, healthcare providers, foundations and academia, the Forum is a public/private partnership that is guided by an Executive Committee that sets the research agenda. The Forum organizes roundtables and issues reports on a range of global HIV/AIDS issues, including treatment-related toxicities, immune-based therapies, health services research, co-infections, prevention, and the transference of research results into care. Forum recommendations have changed how clinical trials are conducted, accelerated the delivery of new classes of drugs, heightened awareness of TB/HIV co-infection, and helped to spur national momentum toward universal testing for HIV. http://www.hivforum.org/
SOURCE Forum for Collaborative HIV Research
Source
December 6 at a major scientific meeting – Advancing HCV Drug Development: A Collaborative Approach – convened by the Forum for Collaborative HIV Research, researchers, hepatitis advocates, members of industry and representatives from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) created the roadmap for accelerating the development of DAAs, agreeing that this new class of drugs targeting specific hepatitis C virus proteins has the same potential to improve treatment outcomes for people with HCV as antiretroviral drugs changed the standard of care in HIV. Currently, two DAA compounds have advanced into phase 3 development in the United State and EU, and many more are in phase 2 trials and likely to advance to phase 3 research in the near future.
"If there was ever a time when we can change the course of HCV, it is now," said Veronica Miller, Ph.D., Director of the Forum. "We are now where we were with HIV more than a decade ago and can apply many of the lessons learned from HIV drug development to significantly accelerate the progress in bringing new and better HCV therapies to market."
DAAs directly attack the ability of the hepatitis C virus to replicate and can increase the cure rate in certain HCV patients to between 60 and 70 percent– a major advance over the 40 percent success rate associated with the currently recommended treatment for chronic HCV infection, the combination of pegylated interferon and ribavirin. Although the first DAAs still require concomitant use with current HCV medications, these new compounds will shorten the length of time on pegylated interferon and ribavirin therapy, which hepatitis specialists noted is often difficult to tolerate and has significant adverse event profiles that limit treatment in many patients. According to the latest data, between 15 and 30 percent of HCV patients started on current HCV therapy are unable to complete the year of treatment now required because they cannot tolerate the side effects.
Charting the future of HCV drug development, the meeting participants applied FDA's new guidance on conducting clinical trials on DAAs, which was issued in September 2010 in draft form and expected to be finalized in 2011. According to Jeffrey S. Murray, M.D., M.P.H., Deputy Director of the Division of Antiviral Drug Products in FDA's Center for Drug Evaluation and Research, the draft guidance follows the same approach FDA uses in developing HIV and oncology drugs. For early clinical testing, FDA recognizes that most if not all DAAs for HCV will be used in combination with other approved drug and therefore, recommends studies examining the relationship between the new DAA agent and both pegylated interferon and ribavirin as well as testing the combination antiviral activity. FDA's draft guidance also calls for using the results from proof-in-concept trials (meaning a study in HCV infected patients that demonstrates initial activity as measured by reductions in the HCV viral load) to guide dose selection for subsequent Phase 2 trials in which DAAs are studied for longer durations as part of a combination regimen. FDA is further encouraging drug sponsors to design development plans for combinations of two or more DAAs.
"The good news for the HCV community is that more drugs are coming," said Jur Strobos, MD, JD, FACEP, Deputy Director of the Forum. "The bad news is we don't know how to combine them and that is what we need to study."
With FDA's guidance as the framework, the hepatitis experts also identified the major factors researchers must take into account when designing clinical trials for DAAs and other new HCV therapies. Among the major issues cited are the emergence of resistant virus and its potential management, and including in future DAA clinical trials those special populations with significant unmet needs in HCV therapy. These patients include individuals co-infected with HIV, liver transplant recipients, patients with decompensated cirrhosis, opioid users and those on opiate substitution therapy, and children. According to the Centers for Disease Control and Prevention (CDC), between 5 and 6 percent of infants born to HCV infected women contract the infection from their mothers and the majority of those infants will develop a chronic infection.
Focusing on the special needs of pediatric patients, leaders from both FDA and EMA agreed that the time to start investigating DAAs in children is when sufficient safety data exist in adults. As explained by specialists in pediatric liver disease, children with HCV often tolerate drug therapy better than adults, which is why the ideal age to start children in pediatric trials for DAAs is when they are 3 years old. According to hepatitis experts, the beneficial impact of a 'cure' for children, preferably before they start school, cannot be overestimated.
Reducing Disparities in HCV Clinical Trials
Because identifying potential differences among groups treated with a therapeutic regimen is an important goal of human studies, the HCV community singled out the under-representation of women, older people and different ethnic subgroups in clinical trials as the problem requiring immediate attention and change at a systemic level. Although there is a higher prevalence of HCV in men than women, women metabolize HCV drugs differently and are more affected by autoimmune diseases, which share similar symptoms with HCV. Women also are twice as likely as men to suffer from depression, which is a common side effect of treatment with HCV medications.
Even more challenging for the HCV community is increasing the representation of older HCV-infected adults in HCV clinical trials, even though Baby Boomers constitute the majority of hepatitis C infections in the United States and are often less responsive than younger generations to antiviral treatment. Compounding the problem, older HCV patients are more difficult to treat, due to the increased prevalence of co-morbid conditions, such as diabetes, dyslipidemia, and other metabolic conditions that are correlated to chronic liver disease. Aging is also strongly associated with liver fibrosis progression, which means older HCV patients are likely to have advanced liver disease and a high risk for impending liver complications. But despite this reality, few studies have examined the age-specific factors of chronic HCV infection and the clinical management of the infection in this patient population.
More than an issue of fairness, HCV experts associate better designed clinical research studies with the increased ability of scientists to catalog and understand the influence of genetic and non-genetic factors on individual and group responses to new treatments. Findings from the large amount of genetic data generated to date show that more than 90 percent of the observed genetic variations occur within, rather than between groups. This underscores the fact that gender and ethnicity have biomedical consequences when evaluating patients with more resistant virus and with more severe disease.
Designing the Research Roadmap to Address a Growing Public Health Threat
Accelerating the development of DAAs to improve HCV treatment outcomes is especially warranted now that the hepatitis C virus has become the most common chronic blood borne infection in the U.S. According to new government estimates, approximately 4.1 million Americans are infected with HCV, of whom 60 to 70 percent will develop chronic liver disease. Currently, almost half of all liver transplants in the U.S. are performed for end-stage hepatitis C. Moreover, because liver disease is one of the leading causes of death in the U.S., the CDC predicts that deaths from chronic liver disease attributed to hepatitis C will double or triple over the next 15 to 20 years.
To change these statistics, hepatitis specialists focused on ways to advance HCV drug development so DAAs and other new classes of drugs for HCV can reach the market quickly. Here, the experts reached agreement on a number of issues:
• Exposure to new single agents – because HCV remains sensitive to ribavirin and pegylated interferon, longer initial studies may be recommended to evaluate single drugs and novel combinations of drugs
• Composition of patients in early studies (phase 1 and 2a) – early studies should be large enough so results with one type of virus or one group of patients can be easily discerned. Focusing on specific genetic sub-populations will also ensure that early studies do not produce confusing results
• Drug resistance in HCV patients – unlike HIV, drug resistance in HCV may not be as large a concern because HCV does not integrate into host DNA as HIV does. Thus, resistant strains are not archived and there is the potential that resistant patients can be retreated with different combinations regimens, as and when they become available
• Baseline parameters – there is the need to develop predictive algorithms based on baseline characteristics such as gender, body weight, HCV genotypes and subtypes
• Exclusion of former and current drug users in clinical trials – exclusion is unnecessary and does not serve the field well. Over 60 percent of patients with HCV are infected through drug use, indicating the need to have quality data to guide treatment decisions in this patient population
As a next step, the Forum for Collaborative HIV Research will publish the consensus of this scientific meeting to advance the research agenda. Once published, the report will be distributed widely to the Forum's many constituencies – government, industry, patient advocates, healthcare providers, foundations, health insurers and academia – with the goal of advancing research on HCV and driving public policy.
About the Forum for Collaborative HIV Research
Now part of the University of California (UC), Berkeley School of Public Health and based in Washington, DC, the Forum was founded in 1997 as the outgrowth of a White House initiative which called for an ongoing collaboration among stakeholders to address emerging issues in HIV/AIDS and set the research strategy. Representing government, industry, patient advocates, healthcare providers, foundations and academia, the Forum is a public/private partnership that is guided by an Executive Committee that sets the research agenda. The Forum organizes roundtables and issues reports on a range of global HIV/AIDS issues, including treatment-related toxicities, immune-based therapies, health services research, co-infections, prevention, and the transference of research results into care. Forum recommendations have changed how clinical trials are conducted, accelerated the delivery of new classes of drugs, heightened awareness of TB/HIV co-infection, and helped to spur national momentum toward universal testing for HIV. http://www.hivforum.org/
SOURCE Forum for Collaborative HIV Research
Source
Tips for the Media on How to Stop Screwing Up HIV/AIDS Coverage
Kellee Terrell
News Editor, TheBody.com
Posted: December 14, 2010 11:56 AM
This year, we saw a number of medical breakthroughs that made headlines: The discovery of two rare human antibodies that kill 90 percent of all HIV strains, which could provide the basis for a vaccine. The first-ever successful clinical trial of a microbicide, which could bring us one step closer to women being able to have more control over their sexual health. And the finding that pre-exposure prophylaxis can reduce HIV infections among gay men.
This year also brought major events that got heavy news coverage: The XVIII International AIDS Conference in Vienna. The first-ever national HIV/AIDS strategy for the U.S. The return of U.S. AIDS Drug Assistance Program (ADAP) waiting lists, which had been empty, but are now full again. A harsh reminder that you can be imprisoned and potentially executed for being gay in certain countries. And a confirmation that poverty is the top risk factor for HIV among heterosexuals living in inner cities.
On the pop culture end, HIV was also present. Part of the porn industry temporarily shut down when adult film actor Derrick Burts tested positive. Project Runway's Mondo Guerra disclosed his status on air. The Other City, a documentary about HIV/AIDS in Washington, D.C., debuted to rave reviews. And on World AIDS Day, celebrities "died" on social media, only to have some billionaire "resuscitate" them when it looked as if they might not be able to raise enough money to do so through smaller donations.
But even in the wake of all of this, the media still doesn't report enough about the global pandemic and, most importantly, there are not enough stories exploring the U.S. epidemic. (Newsflash: AIDS is still a huge problem here in the U.S.) And when the media does tackle AIDS in America, too many times it borrows from FOX News' playbook of sensationalism, fabrications and one-sided narratives.
Just how many down low and criminalization stories can a person take?
And this is where I come in. I looked over 2010's media coverage of HIV/AIDS and came up with some important lessons that journalists should keep in mind for next year:
Include More Voices of People Living With HIV: This is a "no duh" if we want to eliminate stigma. But minus the media frenzy around Project Runway's Mondo Guerra disclosing his HIV status on air, mainstream media almost never showcases the real voices of people living with HIV.
Wouldn't it be awesome if -- on a day other than World AIDS Day -- we could hear people living with HIV talk about love and marriage; stigma and discrimination; pregnancy and family; treatment and adhering to drugs; the trials and tribulations of being on an ADAP waiting list; disclosing to others; and all that other good stuff? Perhaps "reality" only works for the Kardashians.
Bigwigs Are Not the Only People You Should Pay Attention To: Did you know that, this summer at the XVIII International AIDS Conference in Vienna, sex workers from around the world had a major presence (including a huge rally)? Or that the same was true of drug users, who had an international declaration on their behalf signed by more than 18,000 people? Did you know that UNIFEM and the ATHENA Network released a comprehensive report that highlighted the lack of female leadership in HIV policymaking despite the fact that the global face of AIDS is more female than male?
Of course you did. But the rest of the world probably did not: All of those stories were overlooked, because journalists were more interested in writing about Bill Gates, Annie Lennox and other high-power players who were present at the conference. Please don't forget about the grassroots work that is being done to better the lives of people living with HIV. You might be missing out on a good story.
Teens and Seniors Have Sex Too: If it wasn't for the reality shows 16 and Pregnant and Sunset Daze, or the occasional sensationalized stories about "retirement homes gone wild" or "teen sex parties," one would think that these two groups never had sex. Oh, but they do -- and the media (along with most of society) needs to get over its hang-ups and begin exploring the alarming and rising rates of HIV and other sexually transmitted diseases among these demographics. This means fewer interviews with Bristol Palin and company, and more interviews with women such as Marvelyn Brown and Jane Fowler.
The Fight for LGBT Equality Is Connected to HIV Risk: While the media continues to improve its reporting on LGBT issues -- especially around bullying, homophobia, DADT (the U.S. military's "Don't Ask, Don't Tell" law), marriage equality and job discrimination -- more needs to be done to illustrate how these issues directly impact one's own HIV risk.
It may come as a surprise to some that there are still many cases (and many states) in which it is legal to fire someone based on their sexual orientation and gender identity and expression in the U.S. And if people can be fired from their job, that means they can lose their financial stability. They become less able to look after their health care, and in some cases may even become homeless. A slew of reasons begin to emerge that can make those individuals more vulnerable to HIV.
(Hint, hint: National LGBT organizations, perhaps now is the time to make HIV/AIDS a platform issue. If you do, the media might follow.)
Try Normalizing HIV; It's Not That Hard: HIV has always been the "cheese that stands alone" -- it's even classified separately from other sexually transmitted diseases. One way to help destigmatize the disease is to include a discussion about HIV into stories in which HIV is simply a fact to be noted, not the focus of the entire piece. For example, in a feature about people struggling to pay for their health care or the difficulties of adhering to daily medications, why not include a person living with HIV as one of the interviewees? Or in a story about Mother's Day, or Valentine's Day, or Veteran's Day, why not include the perspective of an HIV-positive person? HIV doesn't always have to exist outside the box.
Read the rest of the lessons here.
Want to learn more about the major HIV/AIDS developments, trends and advocates who rocked 2010? Take a look at TheBody.com's new series, HIV/AIDS Year in Review: Looking Back on 2010 (and Ahead to 2011).
Source
News Editor, TheBody.com
Posted: December 14, 2010 11:56 AM
This year, we saw a number of medical breakthroughs that made headlines: The discovery of two rare human antibodies that kill 90 percent of all HIV strains, which could provide the basis for a vaccine. The first-ever successful clinical trial of a microbicide, which could bring us one step closer to women being able to have more control over their sexual health. And the finding that pre-exposure prophylaxis can reduce HIV infections among gay men.
This year also brought major events that got heavy news coverage: The XVIII International AIDS Conference in Vienna. The first-ever national HIV/AIDS strategy for the U.S. The return of U.S. AIDS Drug Assistance Program (ADAP) waiting lists, which had been empty, but are now full again. A harsh reminder that you can be imprisoned and potentially executed for being gay in certain countries. And a confirmation that poverty is the top risk factor for HIV among heterosexuals living in inner cities.
On the pop culture end, HIV was also present. Part of the porn industry temporarily shut down when adult film actor Derrick Burts tested positive. Project Runway's Mondo Guerra disclosed his status on air. The Other City, a documentary about HIV/AIDS in Washington, D.C., debuted to rave reviews. And on World AIDS Day, celebrities "died" on social media, only to have some billionaire "resuscitate" them when it looked as if they might not be able to raise enough money to do so through smaller donations.
But even in the wake of all of this, the media still doesn't report enough about the global pandemic and, most importantly, there are not enough stories exploring the U.S. epidemic. (Newsflash: AIDS is still a huge problem here in the U.S.) And when the media does tackle AIDS in America, too many times it borrows from FOX News' playbook of sensationalism, fabrications and one-sided narratives.
Just how many down low and criminalization stories can a person take?
And this is where I come in. I looked over 2010's media coverage of HIV/AIDS and came up with some important lessons that journalists should keep in mind for next year:
Include More Voices of People Living With HIV: This is a "no duh" if we want to eliminate stigma. But minus the media frenzy around Project Runway's Mondo Guerra disclosing his HIV status on air, mainstream media almost never showcases the real voices of people living with HIV.
Wouldn't it be awesome if -- on a day other than World AIDS Day -- we could hear people living with HIV talk about love and marriage; stigma and discrimination; pregnancy and family; treatment and adhering to drugs; the trials and tribulations of being on an ADAP waiting list; disclosing to others; and all that other good stuff? Perhaps "reality" only works for the Kardashians.
Bigwigs Are Not the Only People You Should Pay Attention To: Did you know that, this summer at the XVIII International AIDS Conference in Vienna, sex workers from around the world had a major presence (including a huge rally)? Or that the same was true of drug users, who had an international declaration on their behalf signed by more than 18,000 people? Did you know that UNIFEM and the ATHENA Network released a comprehensive report that highlighted the lack of female leadership in HIV policymaking despite the fact that the global face of AIDS is more female than male?
Of course you did. But the rest of the world probably did not: All of those stories were overlooked, because journalists were more interested in writing about Bill Gates, Annie Lennox and other high-power players who were present at the conference. Please don't forget about the grassroots work that is being done to better the lives of people living with HIV. You might be missing out on a good story.
Teens and Seniors Have Sex Too: If it wasn't for the reality shows 16 and Pregnant and Sunset Daze, or the occasional sensationalized stories about "retirement homes gone wild" or "teen sex parties," one would think that these two groups never had sex. Oh, but they do -- and the media (along with most of society) needs to get over its hang-ups and begin exploring the alarming and rising rates of HIV and other sexually transmitted diseases among these demographics. This means fewer interviews with Bristol Palin and company, and more interviews with women such as Marvelyn Brown and Jane Fowler.
The Fight for LGBT Equality Is Connected to HIV Risk: While the media continues to improve its reporting on LGBT issues -- especially around bullying, homophobia, DADT (the U.S. military's "Don't Ask, Don't Tell" law), marriage equality and job discrimination -- more needs to be done to illustrate how these issues directly impact one's own HIV risk.
It may come as a surprise to some that there are still many cases (and many states) in which it is legal to fire someone based on their sexual orientation and gender identity and expression in the U.S. And if people can be fired from their job, that means they can lose their financial stability. They become less able to look after their health care, and in some cases may even become homeless. A slew of reasons begin to emerge that can make those individuals more vulnerable to HIV.
(Hint, hint: National LGBT organizations, perhaps now is the time to make HIV/AIDS a platform issue. If you do, the media might follow.)
Try Normalizing HIV; It's Not That Hard: HIV has always been the "cheese that stands alone" -- it's even classified separately from other sexually transmitted diseases. One way to help destigmatize the disease is to include a discussion about HIV into stories in which HIV is simply a fact to be noted, not the focus of the entire piece. For example, in a feature about people struggling to pay for their health care or the difficulties of adhering to daily medications, why not include a person living with HIV as one of the interviewees? Or in a story about Mother's Day, or Valentine's Day, or Veteran's Day, why not include the perspective of an HIV-positive person? HIV doesn't always have to exist outside the box.
Read the rest of the lessons here.
Want to learn more about the major HIV/AIDS developments, trends and advocates who rocked 2010? Take a look at TheBody.com's new series, HIV/AIDS Year in Review: Looking Back on 2010 (and Ahead to 2011).
Source
Amarillo Biosciences Announces Completion of Patient Enrollment in Phase 2 Hepatitis C Trial
Dec 14, 2010 11:08 ET\
AMARILLO, TX--(Marketwire - December 14, 2010) - Amarillo Biosciences, Inc. (ABI) (OTCBB: AMAR) today announced that enrollment in a Phase 2 clinical trial of 165 patients with chronic hepatitis C virus infection is now complete. The clinical trial is being conducted in Taiwan and funded by ABI's strategic partner, CytoPharm, Inc. The aim of the study is to reduce the virologic relapse rate for those patients who have successfully completed standard combination therapy for hepatitis C, which consists of injectable interferon alpha and Ribavirin.
Many patients with hepatitis C are found to be virus-free at the end of standard therapy, but up to half of those with certain viral genotypes relapse in the six months following treatment, once again becoming positive for hepatitis C virus. There are currently no FDA-approved medications shown to reduce the relapse rate for hepatitis C patients, so there is a clear medical need for effective new therapies.
All patients enrolled in this trial first completed standard therapy and were found to be negative for hepatitis C virus. The patients were then assigned to one of two different daily doses of ABI's human interferon alpha lozenges or placebo for 24 weeks, followed by untreated observation for 24 weeks to check for relapse. All patients are scheduled to complete the untreated observation phase by December 2011, and final results from this important study are expected to be available by the end of next year.
About Amarillo Biosciences
Amarillo Biosciences, Inc. is a U.S. biotechnology firm operating in global partnership with the Hayashibara Group, which also holds 5.4% of Amarillo Biosciences shares and has provided over $18 million in loans, grants and equity investments. The Company's primary focus is extensive and ongoing R&D into the use of low-dose, orally administered interferon as a treatment for a variety of conditions, including influenza, hepatitis C, chronic cough, and opportunistic infections in patients who are HIV positive. The Company has invested nearly $40 million to establish oral interferon as a therapeutic agent. The majority of those funds were invested in clinical trials in an effort to achieve FDA approval for interferon. Additional information is available on the web at http://www.amarbio.com/.
Except for the historical information contained herein, the matters discussed in this news release are forward-looking statements that involve risks and uncertainties, including uncertainties related to product development, uncertainties related to the need for regulatory and other government approvals, dependence on proprietary technology, uncertainty of market acceptance of oral interferon or the Company's other product candidates and other risks detailed from time to time in the Company's filings with the Securities and Exchange Commission. In particular, see "Item 1. Description of Business" and "Item 7A. Qualitative and Quantitative Disclosures About Market Risk" of the Company's Form 10-K for the fiscal year ended December 31, 2009.
Investor Relations:
Philippe Niemetz
PAN Consultants, Ltd.
e-mail: p.niemetz@panconsultants.com
Tel: 800-477-7570; 212-344-6464
Fax: 212-618-1276
Joseph M. Cummins, DVM, PhD
Amarillo Biosciences, Inc.
e-mail: jcummins@amarbio.com
Tel: 806-376-1741 x 13
Fax: 806-376-9301
Source
AMARILLO, TX--(Marketwire - December 14, 2010) - Amarillo Biosciences, Inc. (ABI) (OTCBB: AMAR) today announced that enrollment in a Phase 2 clinical trial of 165 patients with chronic hepatitis C virus infection is now complete. The clinical trial is being conducted in Taiwan and funded by ABI's strategic partner, CytoPharm, Inc. The aim of the study is to reduce the virologic relapse rate for those patients who have successfully completed standard combination therapy for hepatitis C, which consists of injectable interferon alpha and Ribavirin.
Many patients with hepatitis C are found to be virus-free at the end of standard therapy, but up to half of those with certain viral genotypes relapse in the six months following treatment, once again becoming positive for hepatitis C virus. There are currently no FDA-approved medications shown to reduce the relapse rate for hepatitis C patients, so there is a clear medical need for effective new therapies.
All patients enrolled in this trial first completed standard therapy and were found to be negative for hepatitis C virus. The patients were then assigned to one of two different daily doses of ABI's human interferon alpha lozenges or placebo for 24 weeks, followed by untreated observation for 24 weeks to check for relapse. All patients are scheduled to complete the untreated observation phase by December 2011, and final results from this important study are expected to be available by the end of next year.
About Amarillo Biosciences
Amarillo Biosciences, Inc. is a U.S. biotechnology firm operating in global partnership with the Hayashibara Group, which also holds 5.4% of Amarillo Biosciences shares and has provided over $18 million in loans, grants and equity investments. The Company's primary focus is extensive and ongoing R&D into the use of low-dose, orally administered interferon as a treatment for a variety of conditions, including influenza, hepatitis C, chronic cough, and opportunistic infections in patients who are HIV positive. The Company has invested nearly $40 million to establish oral interferon as a therapeutic agent. The majority of those funds were invested in clinical trials in an effort to achieve FDA approval for interferon. Additional information is available on the web at http://www.amarbio.com/.
Except for the historical information contained herein, the matters discussed in this news release are forward-looking statements that involve risks and uncertainties, including uncertainties related to product development, uncertainties related to the need for regulatory and other government approvals, dependence on proprietary technology, uncertainty of market acceptance of oral interferon or the Company's other product candidates and other risks detailed from time to time in the Company's filings with the Securities and Exchange Commission. In particular, see "Item 1. Description of Business" and "Item 7A. Qualitative and Quantitative Disclosures About Market Risk" of the Company's Form 10-K for the fiscal year ended December 31, 2009.
Investor Relations:
Philippe Niemetz
PAN Consultants, Ltd.
e-mail: p.niemetz@panconsultants.com
Tel: 800-477-7570; 212-344-6464
Fax: 212-618-1276
Joseph M. Cummins, DVM, PhD
Amarillo Biosciences, Inc.
e-mail: jcummins@amarbio.com
Tel: 806-376-1741 x 13
Fax: 806-376-9301
Source
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