2012
Genotype 4
March 7
Pioglitazone Decreases Hepatitis C Viral Load in Overweight, Treatment Naïve, Genotype 4 Infected-Patients: A Pilot Study
Insulin resistance (IR) is induced by chronic hepatitis C virus (HCV) genotypes 1 and 4 infections. It is not known whether drugs that affect IR such as Pioglitazone and Prednisone also affect serum HCV RNA titers independently of PEG-Interferon-α2/ribavirin treatment. The primary aim was to assess whether Pioglitazone by improving IR and/or inflammation decreases HCV viral load independently of standard of care HCV treatment. A secondary aim was to assess whether Prednisone, a drug that induces insulin resistance and stimulates HCV viral entry and replication in replicon culture systems, increases HCV viral load in this population......
April-March 2012 Annals Of Hepatology
Pegylated interferon-alpha2b plus ribavirin for the treatment of chronic hepatitis C virus genotype 4 infection in patients with normal serum ALT
Jaber Al-Ali, Iqbal Siddique, Rosh Varghese, Fuad Hasan
J Med Virol. 2012 Apr;84(4):601-7. doi: 10.1002/jmv.23215.
Introduction of new subtypes and variants of hepatitis C virus genotype 4 in South Africa.
Gededzha MP, Selabe SG, Kyaw T, Rakgole JN, Blackard JT, Mphahlele MJ.
Source Department of Virology, Medunsa Campus, University of Limpopo/NHLS Dr George Mukhari Tertiary Laboratory, Pretoria, South Africa.
Abstract
Hepatitis C virus (HCV) genotype is an important predictor of disease progression and treatment response. This descriptive study investigated the sequence diversity and genotypes of HCV in South Africa based on comparative analysis of the 5' untranslated region (UTR), C/E1, and NS5B regions of 60 sequences from 52 patients. Genotype distribution in the studied population was as follows: 54% (28/52) were genotype 5, 19% (10/52) were genotype 1, 19% (10/52) were genotype 4, and 2% (1/52) were genotype 3. Three of 52 (6%) individuals were infected with multiple genotypes based on the 5'UTR. Phylogenetic analysis of the 5'UTR was accurate in determining genotypes, while the C/E1 and NS5B coding region was able to differentiate both genotypes and subtypes, including an outlier group. Furthermore, this study observed the existence of distinct variants of HCV which were divergent from confirmed genotype 4 subtypes. For the first time in South Africa, this analysis has shown the presence of HCV subtypes 4k, 4q, and 4r, as well as evidence of intragenotypic recombinant 4l/4q within NS5B. In conclusion, while genotype 5a remains the predominant genotype in South Africa, the current study indicates the introduction of new subtypes and existence of variants of genotype 4 in South Africa. J. Med. Virol. 84:601-607, 2012. © 2011 Wiley Periodicals, Inc.
Copyright © 2012 Wiley Periodicals, Inc.
Feb 13
Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2 to 6: TMC435-C202, a phase IIa, open-label study
Published: January 13, 2012
HCV Infection among Saudi Population: High Prevalence of Genotype 4 and Increased Viral Clearance Rate
HCV is a major etiological agent of liver disease with a high rate of chronic evolution. The virus possesses 6 genotypes with many subtypes. The rate of spontaneous clearance among HCV infected individuals denotes a genetic determinant factor. The current study was designed in order to estimate the rate of HCV infection and ratio of virus clearance among a group of infected patients in Saudi Arabia from 2008 to 2011. It was additionally designed to determine the genotypes of the HCV in persistently infected patients. HCV seroprevalence was conducted on a total of 15,323 individuals. Seropositive individuals were tested by Cobas AmpliPrep/Cobas TaqMan HCV assay to determine the ratio of persistently infected patients to those who showed spontaneous viral clearance. HCV genotyping on random samples from persistently infected patients were conducted based on the differences in the 5′untranslated region (5′UTR). Anti-HCV antibodies were detected in 7.3% of the totally examined sera. A high percentage of the HCV infected individuals experienced virus clearance (48.4%). HCV genotyping revealed the presence of genotypes 1 and 4, the latter represented 97.6% of the tested strains. Evidences of the widespread of the HCV genotype 4 and a high rate of HCV virus clearance were found in Saudi Arabia.
The future for the treatment of genotype 4 chronic hepatitis C
February 2012
Hepatitis C virus genotype 4 (HCV-4) is the most common type of hepatitis C virus (HCV) in the Middle East and Africa, in particular Egypt. Since the development of new protease inhibitors, the response of HCV-4 to the standard regimen of treatment (pegylated interferon/ribavirin) lags behind other genotypes and has become the most resistant type to treat. The development of therapeutic strategies for all patients with HCV-4 whether they are naïve, have experienced a virological breakthrough, are relapsers or non-responders is still a considerable challenge. New types of interferon (Consensus Interferon, Y-shaped, Albinterferon…) and new direct action antiviral drugs (Nitazoxanide, Vit.D, other) may improve the treatment of patients with HCV-4. The IL28B CC polymorphism may be associated with sustained virological response.
Nov. 8, 2011
AASLD-Interim results On Daclatasvir (BMS-790052)W-Peg/Riba In naive geno1/4 Hepatitis C Patients
Bristol-Myers Squibb Company today announced interim results from a Phase IIb clinical trial (COMMAND-1) of 395 treatment-naive, genotype 1 and 4 hepatitis C infected patients in which two doses of the investigational NS5A replication complex inhibitor daclatasvir (BMS-790052), in combination with peginterferon alfa and ribavirin (alfa/RBV), achieved higher virologic response rates through Week 12 than the alfa/RBV control group, with comparable rates of adverse events. The data were reported at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco...
Nov. 8, 2011, 12:02 p.m. EST
Cytheris Announces Interim Results from ECLIPSE 2 Hepatitis C Multicenter Study of IL-7 in Chronically Infected Genotype 1 and 4 Nonresponders to Standard of Care (SOC) Data from ECLIPSE 2 HCV study shows 4 weeks of IL-7 (CYT107) added to Peginterferon and Ribavirin (SOC) induces a broad immune response associated with HCV viral elimination in genotype 1 and 4 treatment experienced patients defined as non-responders to SOC
PARIS, Nov 08, 2011 (BUSINESS WIRE) -- Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, today announced that data from an interim analysis of its ECLIPSE 2 Phase I/IIa study indicate that treatment with four weeks of the Company's investigative immune-modulator, recombinant human Interleukin-7 (CYT107), added to peginterferon and ribavirin (SOC) in genotype 1 and 4 treatment experienced patients defined as nonresponders to SOC, induces a broad immune response associated with HCV viral clearance in genotype 1 and 4 treatment experienced patients defined as nonresponders to SOC.
"In the current pursuit of higher cure rates and shorter treatment times utilizing combinations of multiple direct acting antivirals, we are hopeful that IL-7 restoration of T cell immune control may represent an alternate, shorter, IFN-free pathway to achievement of viral clearance. The effect has already been observed in chronic LCMV and in 3 patients suffering from Progressive Multifocal Leukoencephalopathy (PML) due to the JC virus," said Francois Habersetzer, MD, Principal Investigator at Strasbourg University Hospitals, Inserm 748, University of Strasbourg, France and Co-Chair of the study. "The current study of safety and activity of CYT107 treatment in genotype 1 and 4 patients resistant to one or multiple lines of SOC focuses on one of the more difficult segments of the HCV patient population and strongly supports the potential of additional studies with this cytokine."
The data were presented during a late breaker poster session (abstract #lb-9:Four weeks of IL-7 (CYT107) added to peginterferon and ribavirin (SOC) induces a broad immune response associated with HCV viral clearance in genotype 1 and 4 treatment experienced patients defined as nonresponders to SOC. Habersetzer F, Payen JL, Rouzier R, Alric L, Andreone P, Grando V, Attali P, Hezode C, Serfaty L, Tambussi G, Benhamou Y, Beq S, Demol P, Croughs T, Morre M, Marcellin P) at The Liver Meeting(R), the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco, November 4-8, 2011.
Interim Results of the Phase I/IIa (ECLIPSE 2) Study
ECLIPSE 2 is an open-label, dose-escalating study (3, 10 and 20ug/kg/week). CYT107 was administered subcutaneously, one injection per week for 4 weeks (D0 to D21), as an add-on therapy to 24 or 48 weeks of SOC, peginterferon and ribavirin. SOC was initiated 9 weeks (median) before CYT107. Six patients were included at each dose level and 6 more if at least 2 patients showed a HCV RNA drop > 2 logs. Patients <18 years, with liver cirrhosis, abnormal bilirubin or AP, HIV or HBV co-infection were excluded. Interim results reported at AASLD focus on the 16 patients treated at 3 or 10 ug/kg/wk.
During the study, there was only one serious adverse event (AE) that did not lead to study drug discontinuation. There were no other SAEs, DLT orclinically relevant abnormalities in biological parameters related to CYT107 treatment. 78.6% of AEs were of grade less-than or equal to 1, primarily injection-site reactions, and no neutralizing IL-7 antibodies were detected.
At D56, consistent with CYT107 results in HIV, CYT107 (10ug/kg/wk) induced (median values):
-- A T cell increase +341 CD4/ul(+168%) and +209 CD8/ul (+179%) more than correcting the initial pre-CYT107-SOC induced lymphopenia (-147/uL CD4)
-- A broadening of the T cell receptor repertoire (TCR) diversity (+25%) in the 4 patients with low diversity at D0 (45%)
-- An increased number of CD3 expressing the a4B7 receptors (+73%)
These increases in T cell counts, diversity and functionality were associated with HCV viral elimination at Week 12 in 1/6 patients treated at 3ug/kg and in 5/12 patients treated at 10ug/kg. At CYT107 initiation, all 6 responding patients had a moderate viral load (<4.5 log/mL), showed an increased rate of viral clearance (+25%), and remained undetectable (median current follow up:11 months).
Summary of Presentation Results
In chronic HCV patients defined as non responders to SOC, CYT107 treatment was safe and expanded both CD4 and CD8 T cells, an effect known to provide an efficient and stable immune response. CYT107 also induces a normalization of the diversity of the TCR repertoire. At 10ug/kg/wk, this effect was associated with an antiviral effect and disappearance of serum HCV RNA in patients nonresponsive to SOC.
These promising results suggest the need for future studies combining direct acting antivirals (DAAs) and CYT107 which act through immune restoration in order to achieve complementary immune and direct antiviral effect to achieve a rapid elimination of HCV RNA under a shortened regimen. In fact, as noted above, 5 of these resistant patients among the 12 treated patients quickly became HCV RNA negative after adding CYT107 to SOC.
"With these initial results in mind, the real breakthrough for IL-7 therapy lies in the administration of CYT107 shortly after the massive antigen drop triggered by treatment with two HCV DAAs, a drop which usually occurs less than two weeks following the start of antiviral treatment" commented Therese Croughs, MD, Chief Medical Officer of Cytheris. "For most HCV patients, we believe this combination of two antivirals with IL-7 could lead to a successful treatment outcome without the use of peginterferon in perhaps as little as 6 weeks: 2 weeks to allow for a sufficient drop in antigen load (contributing to the rescue of PD-1 exhausted T cells) and 4 weeks to induce a broad repertoire of protective central memory T cells and block any viral escape by mutation. With a large expansion of T cells including in lymph nodes, a massive and broad CTL attack on the HCV virus can be reasonably expected with an associated and permanent SVR resulting in viral cure.
In the absence of peginterferon, small molecules inhibiting HCV polymerase or protease will improve HCV eradication rate only if they are powerful enough to achieve a full inhibition of HCV replication and remain active for a sufficient period of time, without inducing viral resistance or drug-drug interaction. The experience gathered with HIV treatment shows that the emergence of resistance to anti-retroviral molecules sharing the same mechanism of action is frequent. Therefore, these molecules may deserve to be combined with a well tolerated immuno-modulating agent such as CYT107 which facilitates their effects by improving the control of HCV infection by the immune system.
About Recombinant Human Interleukin-7 (CYT107)
Recombinant human interleukin-7 (CYT107) is a critical immune-modulator for immune T-cell recovery and enhancement. As a growth factor and cytokine physiologically produced by marrow or thymic stromal cells and other epithelia, IL-7 has a critical and, at some steps, a non-redundant stimulating effect on T lymphocyte development, notably on thymopoiesis and, downstream from the thymus, on homeostatic expansion of peripheral T-cells.
Clinical trials including more than 220 patients in Europe, North America, South Africa and Taiwan have demonstrated the potential of IL-7 to expand and protect CD4 and CD8 T-cells. Currently, Cytheris is conducting multiple international investigations of IL-7 in HIV, HCV, HBV, post-BMT and cancer. Additional studies include a NIAID/NIH-sponsored trial (ICICLE) in idiopathic CD4 lymphocytopenia (ICL); a cancer vaccine study in children with Ewing's sarcoma family of tumors or similar genetic tumors sponsored by US National Cancer Institute; a collaborative study in metastatic breast cancer sponsored by the Centre Leon Berard of Lyon; and, a multi-company/institutional study (EraMune 01) sponsored by ORVACS (the international HIV organization funded by the French Bettencourt Schueller Foundation) aimed at attacking the HIV viral reservoir.
About Cytheris -- www.cytheris.com
Cytheris SA is a privately held clinical-stage biopharmaceutical company focused on research and development of new therapies for immune modulation. These drugs aim at reconstituting and enhancing the immune system of patients suffering from cancer, chronic viral infections such as HCV, HBV and HIV, or lympho-depleting treatments such as chemotherapy, radiotherapy, bone marrow transplantation (BMT) and hematopoietic cell transplantation (HCT). The company operates from its headquarters and laboratories in Issy-les-Moulineaux, a suburb of Paris, and its U.S. subsidiary in Rockville, Maryland.
SOURCE: Cytheris
Published: 1 November 2011
Hepatitis C Genotype-4 Infection: Role of Insulin Resistance in Hepatocellular Carcinoma
Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatocellular carcinoma (HCC) and different HCV genotypes show characteristic variations in their pathological properties. Insulin resistance (IR) occurs early in HCV infection and may synergize with viral hepatitis in HCC development. Egypt has the highest reported rates of HCV infection (predominantly genotype 4) in the world; this study investigated effects of HCV genotype-4 (HCV-4) on prevalence of insulin resistance in chronic hepatitis C (CHC) and HCC in Egyptian patients...
October 2011
Impact of IL28B on treatment outcome in hepatitis C virus G1/4 patients receiving response-guided therapy with peginterferon alpha-2a (40KD)/ribavirin
Abstract
The IL28B genotype is the most important pretreatment predictor of treatment outcome in patients with chronic hepatitis C. The impact of the rs12979860 genotype on relapse was retrospectively evaluated in genotype 1/4 patients who received response-guided therapy with peginterferon alpha-2a 180 μg/week plus ribavirin 1,000/1,200 mg/day in a large, randomized, multicenter study. Patients with a rapid virologic response (RVR: hepatitis C virus [HCV] RNA <50 IU/mL) at week 4 were treated for 24 weeks; those with a slow virologic response (no RVR but undetectable HCV RNA or ≥2-log10 decrease at week 12) were randomized to 48 (group A) or 72 weeks of treatment (group B). Relapse rates were compared by rs12979860 genotype (C/C versus combined T/C or T/T [T/*]) in patients with confirmed end-of-treatment response and known end-of-follow-up status (sustained virologic response [SVR] or relapse). The rs12979860 genotype was determined for 340/551 study participants. In patients with RVR and C/C or T/* genotype, relapse rates were similar (10.7% versus 15.2%). In patients randomized to groups A and B, relapse rates were similar in patients with C/C genotype randomized to group A (26.9%) and group B (20.0%). In contrast, relapse rates in T/* patients differed markedly between groups A and B, overall (42.9% and 18.8%; P < 0.025, respectively) and in those with low (<400,000 IU/mL: 37.5% versus 18.8%) and high (≥400,000 IU/mL: 45.0% versus 18.8%) baseline viral loads. Conclusion: The results suggest that the benefits of extended therapy are restricted to patients with a T allele. Relapse rates are highest in patients with T/* genotype and are markedly higher in slow responders treated for 48 weeks compared with 72 weeks. (HEPATOLOGY 2011;)
Any correlation to HCV genotype/viral load,-ALT, AST, ALP, bilirubin, gender,age-to disease progression?
Disease progression was also independent of all genotypes. Serum ALP, ALT, bilirubin and viremea levels were significantly elevated in patients with genotype 4a...
Insulin resistance and hepatitis C: an evolving story
Genotype-specific abnormalities in postreceptor insulin signalling that could help explain the clinical association of genotypes 1 and 4 with IR have not been clearly elucidated
HCV genotype-specific correlation with serum markers: Higher predictability for Genotype 4a
In conclusion, there was a significant variable response of HCV genotypes with serum markers. Severity of disease is independent of serum marker level in genotype 3a, while the liver damage in genotype 4a may associate with viral cytopathic effect as well as the immune-mediated process. An index using six serum markers may correctly predict genotype 4a in patients with accuracy.≥75%...
Management of hepatitis C virus genotype 4: Recommendations of An International Expert Panel
HCV has been classified into no fewer than six major genotypes and a series of subtypes. Each HCV genotype is unique with respect to its nucleotide sequence, geographic distribution, and response to therapy. Genotypes 1, 2, and 3 are common throughout North America and Europe. HCV genotype 4 (HCV-4) is common in the Middle East and in Africa, where it is responsible for more than 80% of HCV infections. It has recently spread to several European countries. HCV-4 is considered a major cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma, and liver transplantation in these regions. Although HCV-4 is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in the world, it has not been the subject of widespread research. Therefore, this document, drafted by a panel of international experts, aimed to review current knowledge on the epidemiology, natural history, clinical, histological features, and treatment of HCV-4 infections....
PSI-7977 Genotypes 1,4,5,6
Press Release;
Hepatitis C Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV Genotypes
"The trial will evaluate PSI-7977 400mg QD with pegylated interferon and ribavirin in patients with HCV genotype 1, 4, 5 or 6 who have not been treated previously.".....
Click here for Locations and Trial Information
Novel Pegylated Interferon Safer, More Effective Than Current Treatment, Study Shows
The data showed that 14.7% and 16.5% of those with HCV genotypes 1 and 4 who received 180 and 240 mcg of PegIFN-lambda, respectively, experienced a rapid virologic response (RVR) to the novel drug compared with 5.8% of patients with the same HCV genotypes who took PegIFN-alfa-2a (P<0.05). The RVR rate among individuals with genotypes 1 and 4 who received 120 mcg of PegIFN-lambda was 6%.
Retrospective pooled safety analysis of standard- versus high-dose peginterferon alfa-2a (40KD) (PEGASYS) in chronic hepatitis C genotype 1 or 4 patients
Hepatitis C virus genotype 4 therapy: progress and challenges
The hepatitis C virus genotype 4 (HCV-4) is prevalent in Egypt, the Middle East and Africa. Recently, the epidemiology of HCV-4 has changed and this genotype has begun to cross borders and spread to several regions in Europe through immigration and injection drug use. HCV-4 has been considered a difficult-to-treat genotype based on the low sustained virological response (SVR) rates obtained with conventional interferon (IFN)-based regimens. Pegylated interferons (PEG-IFN) plus ribavirin therapy for chronic HCV-4 has been associated with increased SVR rates of more than 60%. Shorter treatment of chronic HCV-4 patients with rapid and early virological responses has been associated with high SVR rates, better compliance, fewer adverse events and lower costs. Despite this progress, the treatment of HCV-4 non-responders, injection drug users, patients coinfected with human immunodeficiency virus, thalassaemic patients, patients on haemodialysis and patients with HCV-4 recurrence after liver transplantation still represents a significant therapeutic challenge. Treatment of HCV-4 has markedly improved, with higher sustained response rates and the possibility of shorter regimens. Despite the recent progress in the treatment of HCV-4, more research is required to optimize current therapy and include genotype 4 patients in clinical trials on emerging therapies such as specifically targeted antiviral therapy for HCV with protease and/or polymerase inhibitors....
Hepatitis C Genotype 4 Spread To Egypt and Africa into Europe
Hepatitis C virus (HCV) genotype 4, previously limited to Egypt and other parts of Africa, has now spread to southern Europe and other parts of world, an international panel says in a review published online December 9th in the Journal of Hepatology.
Genotype 4, or the Egyptian genotype, now accounts for roughly 20% of HCV infections in Europe and worldwide...
Genotype 4
March 7
Pioglitazone Decreases Hepatitis C Viral Load in Overweight, Treatment Naïve, Genotype 4 Infected-Patients: A Pilot Study
Insulin resistance (IR) is induced by chronic hepatitis C virus (HCV) genotypes 1 and 4 infections. It is not known whether drugs that affect IR such as Pioglitazone and Prednisone also affect serum HCV RNA titers independently of PEG-Interferon-α2/ribavirin treatment. The primary aim was to assess whether Pioglitazone by improving IR and/or inflammation decreases HCV viral load independently of standard of care HCV treatment. A secondary aim was to assess whether Prednisone, a drug that induces insulin resistance and stimulates HCV viral entry and replication in replicon culture systems, increases HCV viral load in this population......
April-March 2012 Annals Of Hepatology
Pegylated interferon-alpha2b plus ribavirin for the treatment of chronic hepatitis C virus genotype 4 infection in patients with normal serum ALT
Jaber Al-Ali, Iqbal Siddique, Rosh Varghese, Fuad Hasan
J Med Virol. 2012 Apr;84(4):601-7. doi: 10.1002/jmv.23215.
Introduction of new subtypes and variants of hepatitis C virus genotype 4 in South Africa.
Gededzha MP, Selabe SG, Kyaw T, Rakgole JN, Blackard JT, Mphahlele MJ.
Source Department of Virology, Medunsa Campus, University of Limpopo/NHLS Dr George Mukhari Tertiary Laboratory, Pretoria, South Africa.
Abstract
Hepatitis C virus (HCV) genotype is an important predictor of disease progression and treatment response. This descriptive study investigated the sequence diversity and genotypes of HCV in South Africa based on comparative analysis of the 5' untranslated region (UTR), C/E1, and NS5B regions of 60 sequences from 52 patients. Genotype distribution in the studied population was as follows: 54% (28/52) were genotype 5, 19% (10/52) were genotype 1, 19% (10/52) were genotype 4, and 2% (1/52) were genotype 3. Three of 52 (6%) individuals were infected with multiple genotypes based on the 5'UTR. Phylogenetic analysis of the 5'UTR was accurate in determining genotypes, while the C/E1 and NS5B coding region was able to differentiate both genotypes and subtypes, including an outlier group. Furthermore, this study observed the existence of distinct variants of HCV which were divergent from confirmed genotype 4 subtypes. For the first time in South Africa, this analysis has shown the presence of HCV subtypes 4k, 4q, and 4r, as well as evidence of intragenotypic recombinant 4l/4q within NS5B. In conclusion, while genotype 5a remains the predominant genotype in South Africa, the current study indicates the introduction of new subtypes and existence of variants of genotype 4 in South Africa. J. Med. Virol. 84:601-607, 2012. © 2011 Wiley Periodicals, Inc.
Copyright © 2012 Wiley Periodicals, Inc.
Feb 13
Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2 to 6: TMC435-C202, a phase IIa, open-label study
Published: January 13, 2012
HCV Infection among Saudi Population: High Prevalence of Genotype 4 and Increased Viral Clearance Rate
HCV is a major etiological agent of liver disease with a high rate of chronic evolution. The virus possesses 6 genotypes with many subtypes. The rate of spontaneous clearance among HCV infected individuals denotes a genetic determinant factor. The current study was designed in order to estimate the rate of HCV infection and ratio of virus clearance among a group of infected patients in Saudi Arabia from 2008 to 2011. It was additionally designed to determine the genotypes of the HCV in persistently infected patients. HCV seroprevalence was conducted on a total of 15,323 individuals. Seropositive individuals were tested by Cobas AmpliPrep/Cobas TaqMan HCV assay to determine the ratio of persistently infected patients to those who showed spontaneous viral clearance. HCV genotyping on random samples from persistently infected patients were conducted based on the differences in the 5′untranslated region (5′UTR). Anti-HCV antibodies were detected in 7.3% of the totally examined sera. A high percentage of the HCV infected individuals experienced virus clearance (48.4%). HCV genotyping revealed the presence of genotypes 1 and 4, the latter represented 97.6% of the tested strains. Evidences of the widespread of the HCV genotype 4 and a high rate of HCV virus clearance were found in Saudi Arabia.
The future for the treatment of genotype 4 chronic hepatitis C
February 2012
Hepatitis C virus genotype 4 (HCV-4) is the most common type of hepatitis C virus (HCV) in the Middle East and Africa, in particular Egypt. Since the development of new protease inhibitors, the response of HCV-4 to the standard regimen of treatment (pegylated interferon/ribavirin) lags behind other genotypes and has become the most resistant type to treat. The development of therapeutic strategies for all patients with HCV-4 whether they are naïve, have experienced a virological breakthrough, are relapsers or non-responders is still a considerable challenge. New types of interferon (Consensus Interferon, Y-shaped, Albinterferon…) and new direct action antiviral drugs (Nitazoxanide, Vit.D, other) may improve the treatment of patients with HCV-4. The IL28B CC polymorphism may be associated with sustained virological response.
Nov. 8, 2011
AASLD-Interim results On Daclatasvir (BMS-790052)W-Peg/Riba In naive geno1/4 Hepatitis C Patients
Bristol-Myers Squibb Company today announced interim results from a Phase IIb clinical trial (COMMAND-1) of 395 treatment-naive, genotype 1 and 4 hepatitis C infected patients in which two doses of the investigational NS5A replication complex inhibitor daclatasvir (BMS-790052), in combination with peginterferon alfa and ribavirin (alfa/RBV), achieved higher virologic response rates through Week 12 than the alfa/RBV control group, with comparable rates of adverse events. The data were reported at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco...
Nov. 8, 2011, 12:02 p.m. EST
Cytheris Announces Interim Results from ECLIPSE 2 Hepatitis C Multicenter Study of IL-7 in Chronically Infected Genotype 1 and 4 Nonresponders to Standard of Care (SOC) Data from ECLIPSE 2 HCV study shows 4 weeks of IL-7 (CYT107) added to Peginterferon and Ribavirin (SOC) induces a broad immune response associated with HCV viral elimination in genotype 1 and 4 treatment experienced patients defined as non-responders to SOC
PARIS, Nov 08, 2011 (BUSINESS WIRE) -- Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, today announced that data from an interim analysis of its ECLIPSE 2 Phase I/IIa study indicate that treatment with four weeks of the Company's investigative immune-modulator, recombinant human Interleukin-7 (CYT107), added to peginterferon and ribavirin (SOC) in genotype 1 and 4 treatment experienced patients defined as nonresponders to SOC, induces a broad immune response associated with HCV viral clearance in genotype 1 and 4 treatment experienced patients defined as nonresponders to SOC.
"In the current pursuit of higher cure rates and shorter treatment times utilizing combinations of multiple direct acting antivirals, we are hopeful that IL-7 restoration of T cell immune control may represent an alternate, shorter, IFN-free pathway to achievement of viral clearance. The effect has already been observed in chronic LCMV and in 3 patients suffering from Progressive Multifocal Leukoencephalopathy (PML) due to the JC virus," said Francois Habersetzer, MD, Principal Investigator at Strasbourg University Hospitals, Inserm 748, University of Strasbourg, France and Co-Chair of the study. "The current study of safety and activity of CYT107 treatment in genotype 1 and 4 patients resistant to one or multiple lines of SOC focuses on one of the more difficult segments of the HCV patient population and strongly supports the potential of additional studies with this cytokine."
The data were presented during a late breaker poster session (abstract #lb-9:Four weeks of IL-7 (CYT107) added to peginterferon and ribavirin (SOC) induces a broad immune response associated with HCV viral clearance in genotype 1 and 4 treatment experienced patients defined as nonresponders to SOC. Habersetzer F, Payen JL, Rouzier R, Alric L, Andreone P, Grando V, Attali P, Hezode C, Serfaty L, Tambussi G, Benhamou Y, Beq S, Demol P, Croughs T, Morre M, Marcellin P) at The Liver Meeting(R), the 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco, November 4-8, 2011.
Interim Results of the Phase I/IIa (ECLIPSE 2) Study
ECLIPSE 2 is an open-label, dose-escalating study (3, 10 and 20ug/kg/week). CYT107 was administered subcutaneously, one injection per week for 4 weeks (D0 to D21), as an add-on therapy to 24 or 48 weeks of SOC, peginterferon and ribavirin. SOC was initiated 9 weeks (median) before CYT107. Six patients were included at each dose level and 6 more if at least 2 patients showed a HCV RNA drop > 2 logs. Patients <18 years, with liver cirrhosis, abnormal bilirubin or AP, HIV or HBV co-infection were excluded. Interim results reported at AASLD focus on the 16 patients treated at 3 or 10 ug/kg/wk.
During the study, there was only one serious adverse event (AE) that did not lead to study drug discontinuation. There were no other SAEs, DLT orclinically relevant abnormalities in biological parameters related to CYT107 treatment. 78.6% of AEs were of grade less-than or equal to 1, primarily injection-site reactions, and no neutralizing IL-7 antibodies were detected.
At D56, consistent with CYT107 results in HIV, CYT107 (10ug/kg/wk) induced (median values):
-- A T cell increase +341 CD4/ul(+168%) and +209 CD8/ul (+179%) more than correcting the initial pre-CYT107-SOC induced lymphopenia (-147/uL CD4)
-- A broadening of the T cell receptor repertoire (TCR) diversity (+25%) in the 4 patients with low diversity at D0 (45%)
-- An increased number of CD3 expressing the a4B7 receptors (+73%)
These increases in T cell counts, diversity and functionality were associated with HCV viral elimination at Week 12 in 1/6 patients treated at 3ug/kg and in 5/12 patients treated at 10ug/kg. At CYT107 initiation, all 6 responding patients had a moderate viral load (<4.5 log/mL), showed an increased rate of viral clearance (+25%), and remained undetectable (median current follow up:11 months).
Summary of Presentation Results
In chronic HCV patients defined as non responders to SOC, CYT107 treatment was safe and expanded both CD4 and CD8 T cells, an effect known to provide an efficient and stable immune response. CYT107 also induces a normalization of the diversity of the TCR repertoire. At 10ug/kg/wk, this effect was associated with an antiviral effect and disappearance of serum HCV RNA in patients nonresponsive to SOC.
These promising results suggest the need for future studies combining direct acting antivirals (DAAs) and CYT107 which act through immune restoration in order to achieve complementary immune and direct antiviral effect to achieve a rapid elimination of HCV RNA under a shortened regimen. In fact, as noted above, 5 of these resistant patients among the 12 treated patients quickly became HCV RNA negative after adding CYT107 to SOC.
"With these initial results in mind, the real breakthrough for IL-7 therapy lies in the administration of CYT107 shortly after the massive antigen drop triggered by treatment with two HCV DAAs, a drop which usually occurs less than two weeks following the start of antiviral treatment" commented Therese Croughs, MD, Chief Medical Officer of Cytheris. "For most HCV patients, we believe this combination of two antivirals with IL-7 could lead to a successful treatment outcome without the use of peginterferon in perhaps as little as 6 weeks: 2 weeks to allow for a sufficient drop in antigen load (contributing to the rescue of PD-1 exhausted T cells) and 4 weeks to induce a broad repertoire of protective central memory T cells and block any viral escape by mutation. With a large expansion of T cells including in lymph nodes, a massive and broad CTL attack on the HCV virus can be reasonably expected with an associated and permanent SVR resulting in viral cure.
In the absence of peginterferon, small molecules inhibiting HCV polymerase or protease will improve HCV eradication rate only if they are powerful enough to achieve a full inhibition of HCV replication and remain active for a sufficient period of time, without inducing viral resistance or drug-drug interaction. The experience gathered with HIV treatment shows that the emergence of resistance to anti-retroviral molecules sharing the same mechanism of action is frequent. Therefore, these molecules may deserve to be combined with a well tolerated immuno-modulating agent such as CYT107 which facilitates their effects by improving the control of HCV infection by the immune system.
About Recombinant Human Interleukin-7 (CYT107)
Recombinant human interleukin-7 (CYT107) is a critical immune-modulator for immune T-cell recovery and enhancement. As a growth factor and cytokine physiologically produced by marrow or thymic stromal cells and other epithelia, IL-7 has a critical and, at some steps, a non-redundant stimulating effect on T lymphocyte development, notably on thymopoiesis and, downstream from the thymus, on homeostatic expansion of peripheral T-cells.
Clinical trials including more than 220 patients in Europe, North America, South Africa and Taiwan have demonstrated the potential of IL-7 to expand and protect CD4 and CD8 T-cells. Currently, Cytheris is conducting multiple international investigations of IL-7 in HIV, HCV, HBV, post-BMT and cancer. Additional studies include a NIAID/NIH-sponsored trial (ICICLE) in idiopathic CD4 lymphocytopenia (ICL); a cancer vaccine study in children with Ewing's sarcoma family of tumors or similar genetic tumors sponsored by US National Cancer Institute; a collaborative study in metastatic breast cancer sponsored by the Centre Leon Berard of Lyon; and, a multi-company/institutional study (EraMune 01) sponsored by ORVACS (the international HIV organization funded by the French Bettencourt Schueller Foundation) aimed at attacking the HIV viral reservoir.
About Cytheris -- www.cytheris.com
Cytheris SA is a privately held clinical-stage biopharmaceutical company focused on research and development of new therapies for immune modulation. These drugs aim at reconstituting and enhancing the immune system of patients suffering from cancer, chronic viral infections such as HCV, HBV and HIV, or lympho-depleting treatments such as chemotherapy, radiotherapy, bone marrow transplantation (BMT) and hematopoietic cell transplantation (HCT). The company operates from its headquarters and laboratories in Issy-les-Moulineaux, a suburb of Paris, and its U.S. subsidiary in Rockville, Maryland.
SOURCE: Cytheris
Published: 1 November 2011
Hepatitis C Genotype-4 Infection: Role of Insulin Resistance in Hepatocellular Carcinoma
Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatocellular carcinoma (HCC) and different HCV genotypes show characteristic variations in their pathological properties. Insulin resistance (IR) occurs early in HCV infection and may synergize with viral hepatitis in HCC development. Egypt has the highest reported rates of HCV infection (predominantly genotype 4) in the world; this study investigated effects of HCV genotype-4 (HCV-4) on prevalence of insulin resistance in chronic hepatitis C (CHC) and HCC in Egyptian patients...
October 2011
Impact of IL28B on treatment outcome in hepatitis C virus G1/4 patients receiving response-guided therapy with peginterferon alpha-2a (40KD)/ribavirin
Abstract
The IL28B genotype is the most important pretreatment predictor of treatment outcome in patients with chronic hepatitis C. The impact of the rs12979860 genotype on relapse was retrospectively evaluated in genotype 1/4 patients who received response-guided therapy with peginterferon alpha-2a 180 μg/week plus ribavirin 1,000/1,200 mg/day in a large, randomized, multicenter study. Patients with a rapid virologic response (RVR: hepatitis C virus [HCV] RNA <50 IU/mL) at week 4 were treated for 24 weeks; those with a slow virologic response (no RVR but undetectable HCV RNA or ≥2-log10 decrease at week 12) were randomized to 48 (group A) or 72 weeks of treatment (group B). Relapse rates were compared by rs12979860 genotype (C/C versus combined T/C or T/T [T/*]) in patients with confirmed end-of-treatment response and known end-of-follow-up status (sustained virologic response [SVR] or relapse). The rs12979860 genotype was determined for 340/551 study participants. In patients with RVR and C/C or T/* genotype, relapse rates were similar (10.7% versus 15.2%). In patients randomized to groups A and B, relapse rates were similar in patients with C/C genotype randomized to group A (26.9%) and group B (20.0%). In contrast, relapse rates in T/* patients differed markedly between groups A and B, overall (42.9% and 18.8%; P < 0.025, respectively) and in those with low (<400,000 IU/mL: 37.5% versus 18.8%) and high (≥400,000 IU/mL: 45.0% versus 18.8%) baseline viral loads. Conclusion: The results suggest that the benefits of extended therapy are restricted to patients with a T allele. Relapse rates are highest in patients with T/* genotype and are markedly higher in slow responders treated for 48 weeks compared with 72 weeks. (HEPATOLOGY 2011;)
Any correlation to HCV genotype/viral load,-ALT, AST, ALP, bilirubin, gender,age-to disease progression?
Disease progression was also independent of all genotypes. Serum ALP, ALT, bilirubin and viremea levels were significantly elevated in patients with genotype 4a...
Insulin resistance and hepatitis C: an evolving story
Genotype-specific abnormalities in postreceptor insulin signalling that could help explain the clinical association of genotypes 1 and 4 with IR have not been clearly elucidated
HCV genotype-specific correlation with serum markers: Higher predictability for Genotype 4a
In conclusion, there was a significant variable response of HCV genotypes with serum markers. Severity of disease is independent of serum marker level in genotype 3a, while the liver damage in genotype 4a may associate with viral cytopathic effect as well as the immune-mediated process. An index using six serum markers may correctly predict genotype 4a in patients with accuracy.≥75%...
Management of hepatitis C virus genotype 4: Recommendations of An International Expert Panel
HCV has been classified into no fewer than six major genotypes and a series of subtypes. Each HCV genotype is unique with respect to its nucleotide sequence, geographic distribution, and response to therapy. Genotypes 1, 2, and 3 are common throughout North America and Europe. HCV genotype 4 (HCV-4) is common in the Middle East and in Africa, where it is responsible for more than 80% of HCV infections. It has recently spread to several European countries. HCV-4 is considered a major cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma, and liver transplantation in these regions. Although HCV-4 is the cause of approximately 20% of the 170 million cases of chronic hepatitis C in the world, it has not been the subject of widespread research. Therefore, this document, drafted by a panel of international experts, aimed to review current knowledge on the epidemiology, natural history, clinical, histological features, and treatment of HCV-4 infections....
PSI-7977 Genotypes 1,4,5,6
Press Release;
Hepatitis C Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV Genotypes
"The trial will evaluate PSI-7977 400mg QD with pegylated interferon and ribavirin in patients with HCV genotype 1, 4, 5 or 6 who have not been treated previously.".....
Click here for Locations and Trial Information
Novel Pegylated Interferon Safer, More Effective Than Current Treatment, Study Shows
The data showed that 14.7% and 16.5% of those with HCV genotypes 1 and 4 who received 180 and 240 mcg of PegIFN-lambda, respectively, experienced a rapid virologic response (RVR) to the novel drug compared with 5.8% of patients with the same HCV genotypes who took PegIFN-alfa-2a (P<0.05). The RVR rate among individuals with genotypes 1 and 4 who received 120 mcg of PegIFN-lambda was 6%.
Retrospective pooled safety analysis of standard- versus high-dose peginterferon alfa-2a (40KD) (PEGASYS) in chronic hepatitis C genotype 1 or 4 patients
Hepatitis C virus genotype 4 therapy: progress and challenges
The hepatitis C virus genotype 4 (HCV-4) is prevalent in Egypt, the Middle East and Africa. Recently, the epidemiology of HCV-4 has changed and this genotype has begun to cross borders and spread to several regions in Europe through immigration and injection drug use. HCV-4 has been considered a difficult-to-treat genotype based on the low sustained virological response (SVR) rates obtained with conventional interferon (IFN)-based regimens. Pegylated interferons (PEG-IFN) plus ribavirin therapy for chronic HCV-4 has been associated with increased SVR rates of more than 60%. Shorter treatment of chronic HCV-4 patients with rapid and early virological responses has been associated with high SVR rates, better compliance, fewer adverse events and lower costs. Despite this progress, the treatment of HCV-4 non-responders, injection drug users, patients coinfected with human immunodeficiency virus, thalassaemic patients, patients on haemodialysis and patients with HCV-4 recurrence after liver transplantation still represents a significant therapeutic challenge. Treatment of HCV-4 has markedly improved, with higher sustained response rates and the possibility of shorter regimens. Despite the recent progress in the treatment of HCV-4, more research is required to optimize current therapy and include genotype 4 patients in clinical trials on emerging therapies such as specifically targeted antiviral therapy for HCV with protease and/or polymerase inhibitors....
Hepatitis C Genotype 4 Spread To Egypt and Africa into Europe
Hepatitis C virus (HCV) genotype 4, previously limited to Egypt and other parts of Africa, has now spread to southern Europe and other parts of world, an international panel says in a review published online December 9th in the Journal of Hepatology.
Genotype 4, or the Egyptian genotype, now accounts for roughly 20% of HCV infections in Europe and worldwide...