Alan Franciscus Editor-in-Chief
Hepatitis C Support project
HCV Advocate
The term genotype refers to different genetic variations or strains of hepatitis C. The variance in genetic differences is approximately 1/3 between the different genotypes. There are six major groups or genotypes numbered 1 to 6 although some experts believe that there may be as many as 11. Within each genotype are further divisions called subtypes (for example 1a and 1b) and quasispecies.
HCV constantly changes and mutates as it replicates—more than 1 trillion hepatitis C virions replicate each day. During the replication process, the hepatitis C virus will make ‘bad’ copies or errors in the genetic make-up of the newly replicated viruses. The process of constant mutation helps the virus evade the body’s immune response---when the dominant quasi-species is eradicated, another quasi-species emerges. This requires the immune system to constantly identify and kill the newly emerged variants. This is one of the reasons why so many people develop chronic disease. Scientists believe there are literally millions of different HCV quasispecies in everyone infected with hepatitis C, which are unique to everyone because of the individual’s immune response to HCV and quasispecies constantly change over time. In addition, it has been suggested that quasispecies play a role in disease progression and treatment response, but this is still controversial and more studies are needed to fully appreciate the role of quasi-species.
This variability (genotype, subtypes and quasispecies) of hepatitis C has made it difficult to treat and to develop a vaccine that will protect against all HCV strains although recent advances in vaccine development have been encouraging.
Testing for Genotype, Subtype & Quasispecies
A blood test is required for the genotype test. Generally, a quasispecies test is only performed for research purposes. HCV genotype testing is only done once since the genotype does not change.
Genotype Distribution
HCV genotypes and subtypes are distributed differently in different parts of the world, and certain genotypes predominate in certain areas. Genotypes 1-3 are widely distributed throughout the world. Subtype 1a is prevalent in North and South America, Europe, and Australia. Subtype 1b is common in North America and Europe, and is also found in parts of Asia. Genotype 2 is present in most developed countries, but is less common than genotype 1. Some studies suggest that different types of HCV may be associated with different transmission routes. Subtype 3a appears to be prevalent among injection drug users and it is believed that they were introduced into North American and the United Kingdom with the widespread use of heroin in the 1960s.
Importance of Genotype Information
HCV Genotype information is important because of the role it plays in predicting HCV medical treatment response, treatment duration and the dose of ribavirin. However, it should never be used as a reason to deny treatment.
Prediction of Treatment Response
Genotype information is important because it can be used as a predictor of a positive treatment outcome or response. The sustained virological response rates for pegylated interferon plus ribavirin are much higher in genotype 2 and 3 compared with genotype 1.
Other predictors of treatment response include:
• Age of Patient – younger patients respond more favorably especially people under 30 years old.
• Sex of Patient – women are more likely to respond to therapy than men
• Histological (health of the liver) – people with minimal damage respond better to treatment
• Viral Load – the lower the viral load (less than 800,000 IU/mL) the more likely one is to respond to current medications
• Obesity or high Body Mass Index is associated with lower treatment response rates
• Steatosis or fatty liver reduces the chance of responding to treatment.
• Race—Caucasians and Asians respond better to current HCV medications.
Genotype and Treatment Response
Genotype 1 is considered the most difficult to treat with current HCV medications. However, treatment response rates with the newer forms of pegylated interferon plus ribavirin have been remarkably high--up to a 51% sustained virological response rate (SVR – undetectable viral load six months post treatment). Genotype 2 and 3 respond even better to current medications—up to 80%. There is some evidence that genotype 2 responds better to current HCV therapies than genotype 3, but this needs to be confirmed in prospective studies. The reason that a particular genotype responds to treatment differently is unknown, but it is speculated that specific genotypes of the hepatitis C virus live longer or shorter than others. For example, it has been theorized that genotype 2 and 3 of the hepatitis C virus do not live as long (viral lifecycle) as genotype 1 thus making eradication of genotype 2 and 3 easier.
Genotype and Treatment Duration
Genotype is also a factor in the period of time required to treat with current HCV medications. Generally, genotype 1 is treated for 48 weeks and genotype 2 and 3 are treated for 24 weeks. However, there are studies underway to determine the most optimal treatment duration based on certain factors. For instance, some experts believe that people with genotype 1, high viral load should be treated for 72 weeks instead of 48 weeks to maximize treatment response rates. There are also studies evaluating treating people with genotype 2 for 12 weeks and genotype 3 for 48 weeks.
Genotype and HCV Medication Dosage
Genotype information is also important for establishing the appropriate dose of ribavirin. For instance, people with genotype 2 and 3 are given 800 mg a day of ribavirin (flat dose), whereas the ribavirin dose for people with genotype 1 is dosed by body weight.
Mixed Genotypes
A person can become infected with more than one genotype. Data is almost non-existent on being infected with more than one genotype, but some experts believe it may effect treatment response and HCV disease progression.
Steatosis and Genotype
Steatosis (fatty infiltrates of the liver) is a well recognized feature of hepatitis C infection. Steatosis can contribute to HCV disease progression and lower treatment response although the exact mechanism is not completely understood. People with HCV genotype 3 are more likely to develop steatosis and it is believed that HCV genotype 3 is an independent risk factor and may actually play a direct role in the development of steatosis. It has been reported that when genotype 3 individuals are successful treated that steatosis will generally improve and for some steatosis will disappear.
Genotype and HCV Disease Progression
In regards to genotype and HCV disease progression, early limited data suggested that genotype 1b was associated with a more severe disease progression than in genotype 1a or 2, but further studies have not been able to confirm this observation.
Genotype and Liver Transplantation
Genotype 1 (especially 1b) has been associated with a more rapid fibrosis progression in people who have received a liver transplant.
Source
February 13, 2011
Loving your liver: Organ crucial to good health
Published: Friday, February 11, 2011
By Dr. Allen Yudovich
Henry Ford Health System
Of all the body’s vital organs, the heart is the one that gets the most attention this month. But right underneath it is one of the hardest-working organs we have, our liver. It doesn’t carry the touch of romance the heart does, but it is crucial to our well-being.
Our livers change food into nutrients and filter out harmful substances. The vital functions it performs include:
• converting nutrients into energy, hormones and other essential chemicals;
• cleansing toxic substances (including alcohol) from the blood, then neutralizing or rerouting them for disposal;
• processing drugs;
• storing vitamins, minerals, sugars and iron;
• regulating fat and cholesterol; and
• manufacturing bile -- a fluid that helps digest food.
The liver is also generally very good at keeping itself healthy. When it stops functioning well, the term liver disease is often used. But there are actually many forms of liver disease. When symptoms appear, they may include jaundice (a yellowing of the skin or eyes), abdominal pain, lose of appetite and weight loss, dark urine and pale bowel movements. Sometimes the first indication of a problem is found in the results of liver function tests ordered by a physician.
Cirrhosis
Some forms of liver disease are more common in older adults. Cirrhosis most frequently develops after years of alcohol abuse, although moderate drinkers sometimes develop it as well. Over time, the liver becomes scarred and loses its ability to do what it was designed to. Other liver diseases, including hepatitis B, C and D, can also lead to cirrhosis.
As the disease progresses, symptoms that may develop include nausea, fatigue, itching, vomiting blood and a swollen abdomen.
When cirrhosis is caused by excessive drinking, avoiding alcohol and eating a healthy diet may be beneficial because of the liver’s ability to regenerate itself. Medication is used to treat cirrhosis caused by viral hepatitis.
Cirrhosis is also one of the risk factors for liver cancer, which most often affects people older than 40. It also affects men more frequently than women. Other risk factors include smoking, heavy drinking, hepatitis B and C and cancer in another area of the body.
Liver cancer
Liver cancer can be either primary (meaning it started in the liver) or secondary (beginning elsewhere in the body and spreading to the liver). Secondary liver cancer is far more common than primary, because blood that may carry cancer cells is filtered through the liver.
Symptoms include abdominal pain or swelling, jaundice and weight loss, but these rarely appear in the early stages of the disease. Various tests are used to confirm a cancer diagnosis. These may include a biopsy, CT scan, an MRI, ultrasound and blood tests.
Treatment options include surgery, chemotherapy and radiation, along with newer treatments such as radiofrequency ablation, which uses heat to destroy tumors, and cryosurgery, which uses cold to do the same thing. A liver transplant could also be necessary.
Treatment is most successful when the cancer is diagnosed in an earlier stage and when the patient does not also have cirrhosis.
Hepatitis
All forms of hepatitis are inflammations of the liver. The symptoms are similar to other forms of liver disease, but are often mild. A blood test is needed to confirm a hepatitis diagnosis. Treatment ranges from bed rest and avoiding alcohol to medication, depending on the form of hepatitis someone has.
Primary biliary cirrhosis
This is a chronic inflammation of the liver’s bile ducts that affects women more than men. Those who contract it are usually between 40 and 60 years old. It can lead to cirrhosis and eventually destroy the bile ducts. A healthy diet and medication can alleviate the symptoms, which include itching, fatigue and jaundice. A liver transplant may eventually be recommended.
Alcoholic liver disease
As its name implies, this disease is tied to alcohol abuse, although not all heavy drinkers develop it. Alcoholic liver disease generally develops over a period of years and leads to cirrhosis. Symptoms often don’t appear in the early stages of the disease. When they are present they may include abdominal pain, jaundice, fever, excessive thirst and a loss of appetite. They may also worsen after heavy drinking.
All of the above symptoms could also be indicators of a different illness. Anyone who experiences these symptoms should discuss them with their physician.
Allen Yudovich, M.D., is a gastroenterologist at the Henry Ford Medical Center - Fairlane in Dearborn. For an appointment call (800) HENRYFORD.
Source
By Dr. Allen Yudovich
Henry Ford Health System
Of all the body’s vital organs, the heart is the one that gets the most attention this month. But right underneath it is one of the hardest-working organs we have, our liver. It doesn’t carry the touch of romance the heart does, but it is crucial to our well-being.
Our livers change food into nutrients and filter out harmful substances. The vital functions it performs include:
• converting nutrients into energy, hormones and other essential chemicals;
• cleansing toxic substances (including alcohol) from the blood, then neutralizing or rerouting them for disposal;
• processing drugs;
• storing vitamins, minerals, sugars and iron;
• regulating fat and cholesterol; and
• manufacturing bile -- a fluid that helps digest food.
The liver is also generally very good at keeping itself healthy. When it stops functioning well, the term liver disease is often used. But there are actually many forms of liver disease. When symptoms appear, they may include jaundice (a yellowing of the skin or eyes), abdominal pain, lose of appetite and weight loss, dark urine and pale bowel movements. Sometimes the first indication of a problem is found in the results of liver function tests ordered by a physician.
Cirrhosis
Some forms of liver disease are more common in older adults. Cirrhosis most frequently develops after years of alcohol abuse, although moderate drinkers sometimes develop it as well. Over time, the liver becomes scarred and loses its ability to do what it was designed to. Other liver diseases, including hepatitis B, C and D, can also lead to cirrhosis.
As the disease progresses, symptoms that may develop include nausea, fatigue, itching, vomiting blood and a swollen abdomen.
When cirrhosis is caused by excessive drinking, avoiding alcohol and eating a healthy diet may be beneficial because of the liver’s ability to regenerate itself. Medication is used to treat cirrhosis caused by viral hepatitis.
Cirrhosis is also one of the risk factors for liver cancer, which most often affects people older than 40. It also affects men more frequently than women. Other risk factors include smoking, heavy drinking, hepatitis B and C and cancer in another area of the body.
Liver cancer
Liver cancer can be either primary (meaning it started in the liver) or secondary (beginning elsewhere in the body and spreading to the liver). Secondary liver cancer is far more common than primary, because blood that may carry cancer cells is filtered through the liver.
Symptoms include abdominal pain or swelling, jaundice and weight loss, but these rarely appear in the early stages of the disease. Various tests are used to confirm a cancer diagnosis. These may include a biopsy, CT scan, an MRI, ultrasound and blood tests.
Treatment options include surgery, chemotherapy and radiation, along with newer treatments such as radiofrequency ablation, which uses heat to destroy tumors, and cryosurgery, which uses cold to do the same thing. A liver transplant could also be necessary.
Treatment is most successful when the cancer is diagnosed in an earlier stage and when the patient does not also have cirrhosis.
Hepatitis
All forms of hepatitis are inflammations of the liver. The symptoms are similar to other forms of liver disease, but are often mild. A blood test is needed to confirm a hepatitis diagnosis. Treatment ranges from bed rest and avoiding alcohol to medication, depending on the form of hepatitis someone has.
Primary biliary cirrhosis
This is a chronic inflammation of the liver’s bile ducts that affects women more than men. Those who contract it are usually between 40 and 60 years old. It can lead to cirrhosis and eventually destroy the bile ducts. A healthy diet and medication can alleviate the symptoms, which include itching, fatigue and jaundice. A liver transplant may eventually be recommended.
Alcoholic liver disease
As its name implies, this disease is tied to alcohol abuse, although not all heavy drinkers develop it. Alcoholic liver disease generally develops over a period of years and leads to cirrhosis. Symptoms often don’t appear in the early stages of the disease. When they are present they may include abdominal pain, jaundice, fever, excessive thirst and a loss of appetite. They may also worsen after heavy drinking.
All of the above symptoms could also be indicators of a different illness. Anyone who experiences these symptoms should discuss them with their physician.
Allen Yudovich, M.D., is a gastroenterologist at the Henry Ford Medical Center - Fairlane in Dearborn. For an appointment call (800) HENRYFORD.
Source
New Opportunities in Anti-Hepatitis C Virus Drug Discovery: Targeting NS4B
Antiviral Res. 2011 Feb 1. [Epub ahead of print]
Rai R, Deval J.
Alios BioPharma, South San Francisco, USA.
Abstract
Current therapy for chronic hepatitis C virus (HCV) infection constitutes a combination of pegylated interferon alfa-2a or alpha-2b and ribavirin. Although successful for many patient populations, this regimen has numerous limitations, including non-response, relapse, poor tolerability and long duration of treatment. To address these shortcomings, new small molecule agents are advancing in clinical development. Most of the current clinical candidates act by directly inhibiting key enzymes in the viral life-cycle: the NS5B polymerase, or the NS3/4A protease. Less well-studied, the non-structural 4B (NS4B) protein has recently emerged as an alternative target for Direct-acting Antiviral Agents (DAAs). NS4B is a 27-kDa membrane protein that is primarily involved in the formation of membrane vesicles-also named membranous web-used as scaffold for the assembly of the HCV replication complex. In addition, NS4B contains NTPase and RNA binding activities, as well as anti-apoptotic properties. This review summarizes the current understanding of the structure and functions of NS4B, an essential component of the replication machinery of HCV. In this literature and patent review, we report the recent developments in anti-NS4B drug discovery. These advances open the possibility for future combination therapies with other DAAs.
Copyright © 2011. Published by Elsevier B.V.
PMID: 21295075 [PubMed - as supplied by publisher]
Source
Rai R, Deval J.
Alios BioPharma, South San Francisco, USA.
Abstract
Current therapy for chronic hepatitis C virus (HCV) infection constitutes a combination of pegylated interferon alfa-2a or alpha-2b and ribavirin. Although successful for many patient populations, this regimen has numerous limitations, including non-response, relapse, poor tolerability and long duration of treatment. To address these shortcomings, new small molecule agents are advancing in clinical development. Most of the current clinical candidates act by directly inhibiting key enzymes in the viral life-cycle: the NS5B polymerase, or the NS3/4A protease. Less well-studied, the non-structural 4B (NS4B) protein has recently emerged as an alternative target for Direct-acting Antiviral Agents (DAAs). NS4B is a 27-kDa membrane protein that is primarily involved in the formation of membrane vesicles-also named membranous web-used as scaffold for the assembly of the HCV replication complex. In addition, NS4B contains NTPase and RNA binding activities, as well as anti-apoptotic properties. This review summarizes the current understanding of the structure and functions of NS4B, an essential component of the replication machinery of HCV. In this literature and patent review, we report the recent developments in anti-NS4B drug discovery. These advances open the possibility for future combination therapies with other DAAs.
Copyright © 2011. Published by Elsevier B.V.
PMID: 21295075 [PubMed - as supplied by publisher]
Source
Cirrhosis Patients at Increased Risk of Extrahepatic Cancer
Last Updated: February 07, 2011
Patients with liver cirrhosis have more than double the risk of developing extrahepatic cancer than the general population, and they also have a significantly increased risk of hepatocellular carcinoma, according to a study published in the February issue of Clinical Gastroenterology and Hepatology.
MONDAY, Feb. 7 (HealthDay News) -- Patients with liver cirrhosis have more than double the risk of developing extrahepatic cancer than the general population, and they also have a significantly increased risk of hepatocellular carcinoma (HCC), according to a study published in the February issue of Clinical Gastroenterology and Hepatology.
Evangelos Kalaitzakis, M.D., of the University of Gothenburg in Sweden, and colleagues investigated the incidence of malignant neoplasms in patients diagnosed with cirrhosis between 1994 and 2005. Of the 1,019 patients, 68 percent were men, 48 percent had alcoholic liver disease (ALD), 10 percent had hepatitis C virus (HCV), and 12 percent had both ALD and HCV.
The researchers found that, compared to the general population, patients with cirrhosis were at increased risk of HCC (26-fold); cholangiocarcinoma (13-fold); colorectal cancer (four-fold); and cancers of the esophagus (eight-fold), pancreas (five-fold), and lung (five-fold). HCC occurred more frequently among patients with HCV than other diseases, and the risk of HCC among patients with HCV was similar whether they had ALD or not. Patients with non-ALD cirrhosis were at increased risk for cholangiocarcinoma; whereas, the risk for extrahepatic cancers increased mainly among patients with ALD and cirrhosis.
"This study confirms the association of liver cirrhosis with HCC and further indicates that non-HCC malignant neoplasms may be more common in patients with cirrhosis compared with the general population," the authors write.
Abstract
Full Text (subscription or payment may be required)
Source
Patients with liver cirrhosis have more than double the risk of developing extrahepatic cancer than the general population, and they also have a significantly increased risk of hepatocellular carcinoma, according to a study published in the February issue of Clinical Gastroenterology and Hepatology.
MONDAY, Feb. 7 (HealthDay News) -- Patients with liver cirrhosis have more than double the risk of developing extrahepatic cancer than the general population, and they also have a significantly increased risk of hepatocellular carcinoma (HCC), according to a study published in the February issue of Clinical Gastroenterology and Hepatology.
Evangelos Kalaitzakis, M.D., of the University of Gothenburg in Sweden, and colleagues investigated the incidence of malignant neoplasms in patients diagnosed with cirrhosis between 1994 and 2005. Of the 1,019 patients, 68 percent were men, 48 percent had alcoholic liver disease (ALD), 10 percent had hepatitis C virus (HCV), and 12 percent had both ALD and HCV.
The researchers found that, compared to the general population, patients with cirrhosis were at increased risk of HCC (26-fold); cholangiocarcinoma (13-fold); colorectal cancer (four-fold); and cancers of the esophagus (eight-fold), pancreas (five-fold), and lung (five-fold). HCC occurred more frequently among patients with HCV than other diseases, and the risk of HCC among patients with HCV was similar whether they had ALD or not. Patients with non-ALD cirrhosis were at increased risk for cholangiocarcinoma; whereas, the risk for extrahepatic cancers increased mainly among patients with ALD and cirrhosis.
"This study confirms the association of liver cirrhosis with HCC and further indicates that non-HCC malignant neoplasms may be more common in patients with cirrhosis compared with the general population," the authors write.
Abstract
Full Text (subscription or payment may be required)
Source
HIV-Infected Men at Ongoing Risk for HCV Seroconversion, Study Finds
Norra MacReady
February 7, 2011 — Even with conscientious care and state-of-the-art medication, HIV-infected men are at risk for hepatitis C virus (HCV) seroconversion and should have access to ongoing HCV surveillance, the authors of a new study say. Their findings were published online January 31 and appear in the February print issue of Clinical Infectious Diseases.
HCV has become "a leading cause of non-AIDS related morbidity and mortality for HIV-infected persons in the highly active antiretroviral therapy (HAART) era," lead author Lynn E. Taylor, MD, from Brown University, Providence, Rhode Island, and coauthors write. They estimate that up to 30% of HIV-infected people in the United States are coinfected with HCV.
At this time, the US Public Health Service recommends testing for HCV when a patient is initially diagnosed with HIV infection, but not thereafter. However, reports are now surfacing of acute HCV outbreaks in Europe, Australia, New York, and California among HIV-infected men who have sex with other HIV-infected men and engage in potentially traumatic practices such as unprotected anal sex, use of sex toys, multiple partners, and manual insertion, which may involve some exchange of blood. Because HCV treatment is most effective during the acute stages of infection, "it is vital to diagnose incident HCV infection in HIV-infected persons," the authors say.
For a better idea of the risk for acute HCV infection among HIV-infected men, the researchers studied behavioral and demographic factors associated with HCV antibody seroconversion in men participating in the AIDS Clinical Trial Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) study. The ACTG was established in 1987 by the US Department of Health and Human Services, the National Institute of Allergy and Infectious Diseases, and the National Institutes of Health Division of AIDS, and is the largest HIV clinical trials organization in the world. ALLRT is a randomized cohort study of the long-term immunologic, virologic, pharmacologic, and clinical outcomes associated with the use of HAART by HIV-1-seropositive patients. It was started by ACTG in 2000.
Starting in 2002, patients participating in ALLRT have been tested for HCV on entry, with follow-up testing every 96 weeks beginning in 2006. Seventeen other ACTG-funded trials also test patients for HCV on entry and at various follow-up intervals, between 1996 and 2002. The authors determined the incidence of HCV infection from 1996 to 2008 among men participating in these studies. Of those 2848 patients, 2629 had at least 1 HCV antibody test result, with 264 (10%) of those individuals testing positive at baseline. Of the remaining 2365 patients, 1830 had at least 1 subsequent HCV antibody test and were included in this analysis. Their mean age at the time of the initial negative HCV antibody result was 42 years; other demographic information is shown in the table. The mean interval for HCV testing was 2.8 years for HCV seroconverters and 2.6 years for nonseroconverters.
Table
Characteristic Percentage
Race
* White 57%
* Black 22%
* Hispanic 18%
* Asian/Pacific Islander 2%
* Native American 1%
College-educated 70%
Using HAART 94%
Current or prior injection drug use at study entry 6%
HCV seroconversion occurred in 36 of the men studied (2%), for an overall incidence of .51 cases per 100 person-years. Twenty-five percent of the seroconverters reported a history of injection drug use compared with 5% of patients who remained seronegative (P < .001). However, the authors write, "compared with men with initial HCV antibody positivity, seroconverters were more likely to be white and less likely to be black and were more likely to have never injected drugs and to have attended college."
Patients who seroconverted also were more likely to have an HIV RNA level greater than 400 copies/mL compared with those who did not seroconvert. There is an association between less adherence to the HAART regimen and participation in risky sexual practices, and both of these may have figured in the higher seroconversion rate among patients with a higher viral load, the authors suggest. People in the acute stages of HCV infection are also less tolerant of HAART, which may have contributed to their poor compliance.
There were several study limitations. Only half of the participants underwent follow-up HCV testing at intervals shorter than 3 years, so the authors could not determine exactly when seroconversion occurred in these patients, making it impossible to report incidence trends over time. In addition, 23% of the participants did not undergo any follow-up HCV screening, which raises the possibility of selection bias. However, there was no difference in baseline data between those patients and the patients who did have follow-up testing, so "it is likely that the HCV seroconversions represent the true incidence among HIV-infected patients in care," the authors write.
These findings suggest that HIV-infected patients should undergo regular screening for HCV, the researchers conclude. Early detection "may permit more successful treatment and provide opportunity for intervention to mitigate disease spread among drug-using or sexual partners and education to limit liver damage."
This study was supported in part by the AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse; Lifespan/Tufts/Brown Center for AIDS Research; Center for Drug Abuse and AIDS Research; and the National Institutes of Health. The Miriam Hospital is one of the Clinical 340 Research Sites under Harvard/Partners Clinical Trials Unit. Study authors report various financial relationships with Roche, Vertex, Genentech, BMS, Merck, SciClone, GlaxoSmithKline, Three Rivers, Johnson & Johnson, Regulus, and Tibotec.
Clin Infect Dis. Published online January 31, 2011.
Source
February 7, 2011 — Even with conscientious care and state-of-the-art medication, HIV-infected men are at risk for hepatitis C virus (HCV) seroconversion and should have access to ongoing HCV surveillance, the authors of a new study say. Their findings were published online January 31 and appear in the February print issue of Clinical Infectious Diseases.
HCV has become "a leading cause of non-AIDS related morbidity and mortality for HIV-infected persons in the highly active antiretroviral therapy (HAART) era," lead author Lynn E. Taylor, MD, from Brown University, Providence, Rhode Island, and coauthors write. They estimate that up to 30% of HIV-infected people in the United States are coinfected with HCV.
At this time, the US Public Health Service recommends testing for HCV when a patient is initially diagnosed with HIV infection, but not thereafter. However, reports are now surfacing of acute HCV outbreaks in Europe, Australia, New York, and California among HIV-infected men who have sex with other HIV-infected men and engage in potentially traumatic practices such as unprotected anal sex, use of sex toys, multiple partners, and manual insertion, which may involve some exchange of blood. Because HCV treatment is most effective during the acute stages of infection, "it is vital to diagnose incident HCV infection in HIV-infected persons," the authors say.
For a better idea of the risk for acute HCV infection among HIV-infected men, the researchers studied behavioral and demographic factors associated with HCV antibody seroconversion in men participating in the AIDS Clinical Trial Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) study. The ACTG was established in 1987 by the US Department of Health and Human Services, the National Institute of Allergy and Infectious Diseases, and the National Institutes of Health Division of AIDS, and is the largest HIV clinical trials organization in the world. ALLRT is a randomized cohort study of the long-term immunologic, virologic, pharmacologic, and clinical outcomes associated with the use of HAART by HIV-1-seropositive patients. It was started by ACTG in 2000.
Starting in 2002, patients participating in ALLRT have been tested for HCV on entry, with follow-up testing every 96 weeks beginning in 2006. Seventeen other ACTG-funded trials also test patients for HCV on entry and at various follow-up intervals, between 1996 and 2002. The authors determined the incidence of HCV infection from 1996 to 2008 among men participating in these studies. Of those 2848 patients, 2629 had at least 1 HCV antibody test result, with 264 (10%) of those individuals testing positive at baseline. Of the remaining 2365 patients, 1830 had at least 1 subsequent HCV antibody test and were included in this analysis. Their mean age at the time of the initial negative HCV antibody result was 42 years; other demographic information is shown in the table. The mean interval for HCV testing was 2.8 years for HCV seroconverters and 2.6 years for nonseroconverters.
Table
Characteristic Percentage
Race
* White 57%
* Black 22%
* Hispanic 18%
* Asian/Pacific Islander 2%
* Native American 1%
College-educated 70%
Using HAART 94%
Current or prior injection drug use at study entry 6%
HCV seroconversion occurred in 36 of the men studied (2%), for an overall incidence of .51 cases per 100 person-years. Twenty-five percent of the seroconverters reported a history of injection drug use compared with 5% of patients who remained seronegative (P < .001). However, the authors write, "compared with men with initial HCV antibody positivity, seroconverters were more likely to be white and less likely to be black and were more likely to have never injected drugs and to have attended college."
Patients who seroconverted also were more likely to have an HIV RNA level greater than 400 copies/mL compared with those who did not seroconvert. There is an association between less adherence to the HAART regimen and participation in risky sexual practices, and both of these may have figured in the higher seroconversion rate among patients with a higher viral load, the authors suggest. People in the acute stages of HCV infection are also less tolerant of HAART, which may have contributed to their poor compliance.
There were several study limitations. Only half of the participants underwent follow-up HCV testing at intervals shorter than 3 years, so the authors could not determine exactly when seroconversion occurred in these patients, making it impossible to report incidence trends over time. In addition, 23% of the participants did not undergo any follow-up HCV screening, which raises the possibility of selection bias. However, there was no difference in baseline data between those patients and the patients who did have follow-up testing, so "it is likely that the HCV seroconversions represent the true incidence among HIV-infected patients in care," the authors write.
These findings suggest that HIV-infected patients should undergo regular screening for HCV, the researchers conclude. Early detection "may permit more successful treatment and provide opportunity for intervention to mitigate disease spread among drug-using or sexual partners and education to limit liver damage."
This study was supported in part by the AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases; National Institute on Drug Abuse; Lifespan/Tufts/Brown Center for AIDS Research; Center for Drug Abuse and AIDS Research; and the National Institutes of Health. The Miriam Hospital is one of the Clinical 340 Research Sites under Harvard/Partners Clinical Trials Unit. Study authors report various financial relationships with Roche, Vertex, Genentech, BMS, Merck, SciClone, GlaxoSmithKline, Three Rivers, Johnson & Johnson, Regulus, and Tibotec.
Clin Infect Dis. Published online January 31, 2011.
Source
Triplex nucleic acid testing detected HBV, HIV, HCV before seroconversion
Posted February 8, 2011
Stramer S. N Engl J Med. 2011;364:236-247.
A triplex nucleic acid assay detected potentially infectious hepatitis B virus, hepatitis C virus and HIV after analyzing the serologic, biochemical and molecular features of 3.7 million blood donations, according to study findings.
All blood donations in the US have been screened for hepatitis B surface antigen, but the researchers said a small proportion of donors with antibodies against hepatitis B core antigen in the absence of hepatitis B surface antigen have circulating hepatitis B virus (HBV) DNA and may have a risk of infectivity. Additionally, blood collected during the early window period of HBV infection is highly infectious, but the risk decreases as hepatitis B develops.
In 2008, 2,137,275 donors made a total of 3,694,858 donations. Using the Ultrio assay (Gen-Probe), researchers discovered 26 confirmed infections (nine HBV, 15 hepatitis C virus [HCV] and two HIV), giving the assay a positive predictive value of 35%.
The nine patients with HBV had seronegative HBV DNA-positive samples, and all but one was detected on mini-pool nucleic acid testing. Researchers had expected to find no more than four seronegative HBV DNA-positive samples.
Six infected donors had been vaccinated for HBV. Researchers said routine screening for hepatitis B surface antigen or antibodies against hepatitis B core antigen would not have uncovered those infections.
They said the infections were of “inconsequential clinical significance, but their potential for transmission remains unresolved.”
“Our findings show the efficacy of the HBV vaccine for the prevention of clinical disease but not infection, and the cost of interdicting donations that contain HBV DNA from seronegative donors is high in the face of unknown benefit,” they wrote.
Source
Stramer S. N Engl J Med. 2011;364:236-247.
A triplex nucleic acid assay detected potentially infectious hepatitis B virus, hepatitis C virus and HIV after analyzing the serologic, biochemical and molecular features of 3.7 million blood donations, according to study findings.
All blood donations in the US have been screened for hepatitis B surface antigen, but the researchers said a small proportion of donors with antibodies against hepatitis B core antigen in the absence of hepatitis B surface antigen have circulating hepatitis B virus (HBV) DNA and may have a risk of infectivity. Additionally, blood collected during the early window period of HBV infection is highly infectious, but the risk decreases as hepatitis B develops.
In 2008, 2,137,275 donors made a total of 3,694,858 donations. Using the Ultrio assay (Gen-Probe), researchers discovered 26 confirmed infections (nine HBV, 15 hepatitis C virus [HCV] and two HIV), giving the assay a positive predictive value of 35%.
The nine patients with HBV had seronegative HBV DNA-positive samples, and all but one was detected on mini-pool nucleic acid testing. Researchers had expected to find no more than four seronegative HBV DNA-positive samples.
Six infected donors had been vaccinated for HBV. Researchers said routine screening for hepatitis B surface antigen or antibodies against hepatitis B core antigen would not have uncovered those infections.
They said the infections were of “inconsequential clinical significance, but their potential for transmission remains unresolved.”
“Our findings show the efficacy of the HBV vaccine for the prevention of clinical disease but not infection, and the cost of interdicting donations that contain HBV DNA from seronegative donors is high in the face of unknown benefit,” they wrote.
Source
Inhibitex Receives Fast Track Designation for INX-189 for the Treatment of Chronic Hepatitis C Infections
Posted on: Fri, 11 Feb 2011 07:00:01 EST
ATLANTA, Feb 11, 2011 (BUSINESS WIRE) --
Inhibitex, Inc. (Nasdaq: INHX
PowerRating) today reported that the U.S. Food and Drug Administration ("FDA") has designated the investigation of INX-08189 ("INX-189"), a potent guanosine nucleotide polymerase inhibitor for the treatment of chronic hepatitis C viral infection, as a Fast Track development program. Under the FDA Modernization Act of 1997, Fast Track programs are 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. The characteristics of INX-189 that contributed to it being granted Fast Track status include a high genetic barrier to resistance, its pan-genotypic activity, and once-daily oral dosing.
"The FDA's fast track designation for INX-189 is reflective of its unique features and the need for novel antiviral drugs that demonstrate the potential to provide better clinical outcomes and improved tolerability for the millions of individuals suffering from chronic hepatitis C infection," commented Dr. Joseph Patti, Inhibitex's Chief Scientific Officer and Senior Vice President of Research and Development.
The Company reported interim data from the first two cohorts of its ongoing Phase 1b clinical trial of INX-189 on January 9, 2011 and anticipates completing this trial by the end of the first quarter of 2011.
About HCV and INX-189
Hepatitis C is a disease of the liver caused by HCV. It is estimated that over 4 million Americans and 170 million individuals worldwide are infected with HCV, the majority of which represent chronic infections that can cause liver disease, cirrhosis and cancer. Chronic hepatitis C is the leading cause of liver transplants in the United States.
Inhibitex is developing a series of proprietary nucleotide inhibitors that target the RNA-dependent RNA polymerase (NS5b) of HCV. INX-189 is a protide of a 2'-C-methylguanosine analogue. The Company believes that preclinical and clinical studies of INX-189 completed to-date support its potential as a potent, once-daily, low dose oral therapy amenable to combination with other antivirals for the treatment of patients with all known genotypes of HCV.
About Inhibitex
Inhibitex, Inc. is a biopharmaceutical company focused on developing products to prevent and treat serious infectious diseases. In addition to INX-189, the Company's clinical stage antiviral pipeline includes FV-100, a bicyclic nucleoside inhibitor in Phase II development for the prevention and reduction of shingles-associated pain. The Company also has additional HCV nucleotide polymerase inhibitors in various stages of preclinical development and has licensed the use of its proprietary MSCRAMM(R) protein platform to Pfizer for the development of active staphylococcal vaccines. For additional information about the Company, please visit www.inhibitex.com.
Safe Harbor Statement
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than historical facts included in this press release, including statements regarding the Company's belief that the results of preclinical and clinical studies of INX-189 to-date support its potential as a highly potent, once-daily, oral therapy amenable to combination with other anti-virals for the treatment of patients with all known genotypes of HCV, are forward looking statements. These intentions, expectations, or results may not be achieved in the future and various important factors could cause actual results or events to differ materially from the forward-looking statements that the Company makes, including the risk that; the results of ongoing or future preclinical or clinical studies of INX-189 alone or in combination with other anti-viral compounds not supporting its further development for lack of safety, tolerability, anti-viral activity, or any other reason; either the Company, the FDA, a data safety monitoring board or an investigational review board suspending or terminating the clinical development of INX-189 at any time for lack of safety, tolerability, anti-viral activity, or any other reason; obtaining, maintaining and protecting the intellectual property incorporated into and supporting the commercial viability of the Company's product candidates; and other cautionary statements contained elsewhere herein and in its Annual Report on Form 10-K for the year ended December 31, 2009, as filed with the Securities and Exchange Commission, or SEC, on March 26, 2010, and its Quarterly Report on Form 10-Q for the quarter ended September 30, 2010, as filed with the SEC on November 15, 2010. Given these uncertainties, you should not place undue reliance on these forward-looking statements, which apply only as of the date of this press release.
There may be events in the future that the Company is unable to predict accurately, or over which it has no control. The Company's business, financial condition, results of operations and prospects may change. The Company may not update these forward-looking statements, even though its situation may change in the future, unless it has obligations under the Federal securities laws to update and disclose material developments related to previously disclosed information. The Company qualifies all of the information contained in this press release, and particularly its forward-looking statements, by these cautionary statements.
Inhibitex(R) and MSCRAMM(R) are registered trademarks of Inhibitex, Inc.
SOURCE: Inhibitex, Inc.
Inhibitex, Inc.
Russell H. Plumb, Chief Executive Officer, 678-746-1136
rplumb@inhibitex.com
or
The Trout Group
Lee M. Stern, CFA, 646-378-2922
lstern@troutgroup.com
Source
ATLANTA, Feb 11, 2011 (BUSINESS WIRE) --
Inhibitex, Inc. (Nasdaq: INHX
PowerRating) today reported that the U.S. Food and Drug Administration ("FDA") has designated the investigation of INX-08189 ("INX-189"), a potent guanosine nucleotide polymerase inhibitor for the treatment of chronic hepatitis C viral infection, as a Fast Track development program. Under the FDA Modernization Act of 1997, Fast Track programs are 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. The characteristics of INX-189 that contributed to it being granted Fast Track status include a high genetic barrier to resistance, its pan-genotypic activity, and once-daily oral dosing.
"The FDA's fast track designation for INX-189 is reflective of its unique features and the need for novel antiviral drugs that demonstrate the potential to provide better clinical outcomes and improved tolerability for the millions of individuals suffering from chronic hepatitis C infection," commented Dr. Joseph Patti, Inhibitex's Chief Scientific Officer and Senior Vice President of Research and Development.
The Company reported interim data from the first two cohorts of its ongoing Phase 1b clinical trial of INX-189 on January 9, 2011 and anticipates completing this trial by the end of the first quarter of 2011.
About HCV and INX-189
Hepatitis C is a disease of the liver caused by HCV. It is estimated that over 4 million Americans and 170 million individuals worldwide are infected with HCV, the majority of which represent chronic infections that can cause liver disease, cirrhosis and cancer. Chronic hepatitis C is the leading cause of liver transplants in the United States.
Inhibitex is developing a series of proprietary nucleotide inhibitors that target the RNA-dependent RNA polymerase (NS5b) of HCV. INX-189 is a protide of a 2'-C-methylguanosine analogue. The Company believes that preclinical and clinical studies of INX-189 completed to-date support its potential as a potent, once-daily, low dose oral therapy amenable to combination with other antivirals for the treatment of patients with all known genotypes of HCV.
About Inhibitex
Inhibitex, Inc. is a biopharmaceutical company focused on developing products to prevent and treat serious infectious diseases. In addition to INX-189, the Company's clinical stage antiviral pipeline includes FV-100, a bicyclic nucleoside inhibitor in Phase II development for the prevention and reduction of shingles-associated pain. The Company also has additional HCV nucleotide polymerase inhibitors in various stages of preclinical development and has licensed the use of its proprietary MSCRAMM(R) protein platform to Pfizer for the development of active staphylococcal vaccines. For additional information about the Company, please visit www.inhibitex.com.
Safe Harbor Statement
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than historical facts included in this press release, including statements regarding the Company's belief that the results of preclinical and clinical studies of INX-189 to-date support its potential as a highly potent, once-daily, oral therapy amenable to combination with other anti-virals for the treatment of patients with all known genotypes of HCV, are forward looking statements. These intentions, expectations, or results may not be achieved in the future and various important factors could cause actual results or events to differ materially from the forward-looking statements that the Company makes, including the risk that; the results of ongoing or future preclinical or clinical studies of INX-189 alone or in combination with other anti-viral compounds not supporting its further development for lack of safety, tolerability, anti-viral activity, or any other reason; either the Company, the FDA, a data safety monitoring board or an investigational review board suspending or terminating the clinical development of INX-189 at any time for lack of safety, tolerability, anti-viral activity, or any other reason; obtaining, maintaining and protecting the intellectual property incorporated into and supporting the commercial viability of the Company's product candidates; and other cautionary statements contained elsewhere herein and in its Annual Report on Form 10-K for the year ended December 31, 2009, as filed with the Securities and Exchange Commission, or SEC, on March 26, 2010, and its Quarterly Report on Form 10-Q for the quarter ended September 30, 2010, as filed with the SEC on November 15, 2010. Given these uncertainties, you should not place undue reliance on these forward-looking statements, which apply only as of the date of this press release.
There may be events in the future that the Company is unable to predict accurately, or over which it has no control. The Company's business, financial condition, results of operations and prospects may change. The Company may not update these forward-looking statements, even though its situation may change in the future, unless it has obligations under the Federal securities laws to update and disclose material developments related to previously disclosed information. The Company qualifies all of the information contained in this press release, and particularly its forward-looking statements, by these cautionary statements.
Inhibitex(R) and MSCRAMM(R) are registered trademarks of Inhibitex, Inc.
SOURCE: Inhibitex, Inc.
Inhibitex, Inc.
Russell H. Plumb, Chief Executive Officer, 678-746-1136
rplumb@inhibitex.com
or
The Trout Group
Lee M. Stern, CFA, 646-378-2922
lstern@troutgroup.com
Source
FDA removes full clinical hold on Idenix's HCV drug
Wed Feb 9, 2011 6:12pm EST
* Says to stop development of IDX320
* Says FDA places partial clinical hold on IDX184
* Says HIV drug licensed to Glaxo also put on hold (Adds details)
Feb 9 (Reuters) - Idenix Pharmaceuticals Inc (IDIX.O) said U.S. health regulators have removed the full clinical hold on one of its two experimental hepatitis C drugs, and it ceased the development of the other drug because of a toxicity issue.
In September, the U.S. Food and Drug Administration halted all trials of the experimental drugs after detecting liver function abnormalities in three healthy volunteers during an early-stage study of a combination of the compounds IDX184 and IDX320. [ID:nSGE6860G7]
The company said the observed toxicity in the drug-drug interaction study was likely caused by IDX320.
Idenix, which focuses on treating viral diseases, said the FDA has placed the IDX184 program on partial clinical hold.
It said it expects to initiate a Phase IIb trial of IDX184 in combination with pegylated interferon and antiviral pill ribavirin in the second half of 2011.
The company also said its HIV drug -- licensed to GlaxoSmithKline's (GSK.L) unit ViiV Healthcare -- was placed on a clinical hold by the FDA.
Idenix shares closed at $75.04 Wednesday on Nasdaq. (Reporting by Anand Basu in Bangalore; Editing by Joyjeet Das)
Source
* Says to stop development of IDX320
* Says FDA places partial clinical hold on IDX184
* Says HIV drug licensed to Glaxo also put on hold (Adds details)
Feb 9 (Reuters) - Idenix Pharmaceuticals Inc (IDIX.O) said U.S. health regulators have removed the full clinical hold on one of its two experimental hepatitis C drugs, and it ceased the development of the other drug because of a toxicity issue.
In September, the U.S. Food and Drug Administration halted all trials of the experimental drugs after detecting liver function abnormalities in three healthy volunteers during an early-stage study of a combination of the compounds IDX184 and IDX320. [ID:nSGE6860G7]
The company said the observed toxicity in the drug-drug interaction study was likely caused by IDX320.
Idenix, which focuses on treating viral diseases, said the FDA has placed the IDX184 program on partial clinical hold.
It said it expects to initiate a Phase IIb trial of IDX184 in combination with pegylated interferon and antiviral pill ribavirin in the second half of 2011.
The company also said its HIV drug -- licensed to GlaxoSmithKline's (GSK.L) unit ViiV Healthcare -- was placed on a clinical hold by the FDA.
Idenix shares closed at $75.04 Wednesday on Nasdaq. (Reporting by Anand Basu in Bangalore; Editing by Joyjeet Das)
Source
Medivir Announces Start of Phase 1a Trial of the Hepatitis C Polymerase Inhibitor TMC649128
HUDDINGE, Sweden, February 10, 2011 /PRNewswire/ -- Medivir AB (OMX: MVIR), the emerging research-based specialty pharmaceutical company focused on infectious diseases, today announces the start of a phase 1a clinical trial with TMC649128 intended for the treatment of chronic hepatitis C virus infection.
TMC649128 is a nucleoside NS5B polymerase inhibitor that has already demonstrated an attractive pre-clinical profile. It is anticipated that this profile would see TMC649128 be used in combination with HCV directly acting antiviral agents, given their high genetic barrier to resistance and antiviral activity across multiple HCV genotypes.
In pre-clinical studies, TMC649128 displayed in vitro activity across multiple HCV genotypes and a high genetic barrier to resistance.
The phase 1a trial is a double-blind, randomized, placebo-controlled single-ascending dose trial to assess the safety, tolerability and pharmacokinetics in healthy volunteers and will be conducted in Belgium. TMC649128 is being developed in collaboration with Tibotec Pharmaceuticals.
Milestone payment
Medivir entered a Research and Development agreement in the field of hepatitis C virus polymerase with Ortho Biotech Products LP, an affiliate of Tibotec in May 2008. The development of TMC649128 falls under this agreement and by entering clinical development, a milestone payment of Euro 7 million has been triggered for payment to Medivir.
"We are extremely excited to see TMC649128, our first HCV nucleoside inhibitor, move into clinical development", stated Bertil Samuelsson, CSO of Medivir. "The start of this phase 1a trial underlines Medivir's commitment to the development of novel and innovative hepatitis C treatments. We view nucleoside inhibitors as cornerstone components of future HCV treatment paradigms in combination with directly acting antiviral agents and a TMC649128 component could set them apart from other HCV drug classes."
About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.
About Medivir's Commitment of the HCV Area
Medivir and Tibotec are also jointly developing the once daily protease inhibitor TMC435 for treatment of hepatitis C virus infections (HCV).
About Medivir
Medivir is an emerging research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development. Medivir has a strong R&D portfolio and has recently launched its first product Xerese(TM)/Xerclear(R). Medivir's key pipeline asset, TMC435, a protease inhibitor, is in phase 2b clinical development for Hepatitis C and is partnered with Tibotec Pharmaceuticals.
Xerese(TM)/Xerclear(R) is an innovative treatment for cold sores, which has been approved in both the US and Europe. It is partnered with GlaxoSmithKline to be sold OTC in Europe and Russia and with Meda AB in North America. Medivir has retained the Rx rights for Xerclear(R) in Sweden and Finland.
For more information about Medivir, please visit the Company's website: http://www.medivir.se/
For more information about Medivir, please contact;
Medivir (http://www.medivir.se/)
Rein Piir, CFO & VP Investor Relations
Mobile: +46-708-537-292
M:Communications
Europe: Mary-Jane Elliott / Amber Bielecka /
Nick Francis
Medivir@mcomgroup.com
+44(0)20-7920-2330
USA: Jason Marshall
+1-212-897-5497
SOURCE Medivir
Source
TMC649128 is a nucleoside NS5B polymerase inhibitor that has already demonstrated an attractive pre-clinical profile. It is anticipated that this profile would see TMC649128 be used in combination with HCV directly acting antiviral agents, given their high genetic barrier to resistance and antiviral activity across multiple HCV genotypes.
In pre-clinical studies, TMC649128 displayed in vitro activity across multiple HCV genotypes and a high genetic barrier to resistance.
The phase 1a trial is a double-blind, randomized, placebo-controlled single-ascending dose trial to assess the safety, tolerability and pharmacokinetics in healthy volunteers and will be conducted in Belgium. TMC649128 is being developed in collaboration with Tibotec Pharmaceuticals.
Milestone payment
Medivir entered a Research and Development agreement in the field of hepatitis C virus polymerase with Ortho Biotech Products LP, an affiliate of Tibotec in May 2008. The development of TMC649128 falls under this agreement and by entering clinical development, a milestone payment of Euro 7 million has been triggered for payment to Medivir.
"We are extremely excited to see TMC649128, our first HCV nucleoside inhibitor, move into clinical development", stated Bertil Samuelsson, CSO of Medivir. "The start of this phase 1a trial underlines Medivir's commitment to the development of novel and innovative hepatitis C treatments. We view nucleoside inhibitors as cornerstone components of future HCV treatment paradigms in combination with directly acting antiviral agents and a TMC649128 component could set them apart from other HCV drug classes."
About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The WHO estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.
About Medivir's Commitment of the HCV Area
Medivir and Tibotec are also jointly developing the once daily protease inhibitor TMC435 for treatment of hepatitis C virus infections (HCV).
About Medivir
Medivir is an emerging research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development. Medivir has a strong R&D portfolio and has recently launched its first product Xerese(TM)/Xerclear(R). Medivir's key pipeline asset, TMC435, a protease inhibitor, is in phase 2b clinical development for Hepatitis C and is partnered with Tibotec Pharmaceuticals.
Xerese(TM)/Xerclear(R) is an innovative treatment for cold sores, which has been approved in both the US and Europe. It is partnered with GlaxoSmithKline to be sold OTC in Europe and Russia and with Meda AB in North America. Medivir has retained the Rx rights for Xerclear(R) in Sweden and Finland.
For more information about Medivir, please visit the Company's website: http://www.medivir.se/
For more information about Medivir, please contact;
Medivir (http://www.medivir.se/)
Rein Piir, CFO & VP Investor Relations
Mobile: +46-708-537-292
M:Communications
Europe: Mary-Jane Elliott / Amber Bielecka /
Nick Francis
Medivir@mcomgroup.com
+44(0)20-7920-2330
USA: Jason Marshall
+1-212-897-5497
SOURCE Medivir
Source
February 5, 2011
Great summary of Hepatitis C from Black Poppy Magazine
Black Poppy Magazine
http://www.blackpoppy.org.uk/
Hepatitis C
Once known as Hepatitis Non A Non B, Hepatitis C is being discussed a lot in the using community. Here, BP goes behind the ‘Hep C test’ where many of us stop, discovering why further tests are so important in getting to the bottom of your own Hep C diagnosis.
Research by M.M, B.L, EO
In the last issue, BP ‘introduced’ the liver, briefly discussing what it does and how it does it. This issue, we want to look more closely at a virus that has affected the livers of an estimated 250,000 – 600,000 people in the UK alone, 170 million people worldwide with some 3 million more joining the global ranks each year. BP wanted to find some straightforward answers to some essential questions on Hepatitis C and what you may want to consider if you have been diagnosed Hep C (HCV) positive. (BP will look into treatments for HCV next issue).
Hepatitis C is?…
The actual word “hepatitis’ means inflammation or swelling of the liver. This can be caused by chemicals, drugs, drinking too much alcohol or by different kinds of viruses. Hepatitis C is just one of a number of hepatitis viruses (including A, B,D, E, G) and they are all completely different from one another. It can be hard to get your bead around just how small viruses really are. HCV is estimated to be 80 nanometers in diameter (around 30 billion would fit on this dot {,} – another reason why handwashing before and after injecting is so important; be especially vigilant if someone injects you after they’ve just had a hit – they could have microscopic particles of blood on their fingers and then may place them on your injection site. HCV is known to be remain active outside the body for some time so wash your hands and tell others to wash theirs! The hepatitis C virus is in fact a group of viruses, similar enough to be called HCV virus, yet different enough to be classified into subgroups.
Genotypes
Several families of hepatitis C have been observed around The world and these are known as genotypes, because they differ in their genetic make up. They arc usually classified as HCV genotype 1 ,or 2, or 3, etc. Some genotypes respond better to treatment than others so it is important to identify your genotype when considering treatment for Hep C..
Subtypes
Within each genotype, there are subtypes. These are classified as HCV subtype la, or Ib, Ic, etc and within a subtype, incredibly minute differences will exist among individual viruses, called quasispecies – several million quasispecies would exist within a subtype.
How Might HCV Affect Me?
Hepatitis C affects people differently; some are not affected by it while others can be affected seriously. If you contract hepatitis C, your body will produce antibodies to try and destroy it A HCV lest (referred to as an anti-HCV test) will look for the presence of these antibodies and if found, your result will be HCV antibody positive. However, too many of us stop here, terrified that we now have Hep C. But an antibody positive test is only showing ‘exposure’ to the virus – it does not tell you whether you have ‘active’ virus in the blood. Research shows that of 100 people infected wilh HCV, 25 will clear the virus from their bodies completely with 2-6 months of infection but will continue to carry the antibodies for some time. (These are usually people who were infected when they were younger).
This is why if you have received an HCV antibody positive test, further tests are necessary to determine whether there is still an infection present (see PCR tests opposite) and of course, get yourself some follow up tests for your Hep C, certain discoveries might make all the difference. to help identify the extent of any liver complications or disease – and your suitability for the newer HCV treatments. (BP investigates this next issue). Research estimates the other 75 who do not clear the virus will have ongoing (chronic) infection and some arc at risk of developing complications or liver disease. Of these people, approximately 20 may never experience any noticeable symptoms and although they can still transmit HCV, they won’t develop illness or liver disease.
Symptoms Related to HCV
After 10-15 years, the majority of people with hepatitis C will have developed different levels of liver damage that will result in hepatitis C
Symptoms
These could include;
tiredness and fatigue, headaches, vagueness,
depression, altered sleep patterns, abdominal pain, itches and
rashes, nausea, vomiting
and/or loss of appetite, swelling of the ankles
and/or stomach area, red blotches occurring on the upper body, easy bruising.
Some aspects of the disease are still not fully understood and it can be difficult to predict what will happen for any one person. Symptoms can stay at a certain level and dont always get worse. They can come and go with no real pattern. Over a 40 year period of infection, it is believed that: less than 4% of people with chronic hepatitis C would develop liver failure or liver cancer.. Over a 40 year period, 20% of people with chronic (ongoing) HCV infection will develop cirrhosis of the liver.
I’m Hep C Positive – Now What?
After you receive your antibody positive diagnosis, you can be offered (or request) a referral lo see a specialist. They should then offer you a series of tests such as:
PCR Test, Blood Platelet Count, Liver Function Tests (LFTs), liver Biopsy, Ultrasound or doppler ultrasound, or CT scan
Many doctors advise people with hepatitis C to have the hepatitis A and B vaccinations. Although the viruses are unrelated, such vaccinations will help prevent possible additional liver complications caused by having more than one viral infection at the same time.
What is a PCR Test?
PCR stands for polymerase chain reaction. PCR tests detect or measure the actual hepatitis C virus in a sample of blood There are three types of PCR test – viral detection, viral load and viral genotype. These tests assist people to:
+ Determine whether you may have cleared the virus (but still have antibodies)
+ Determine your level of infectivity
+ Confirm inconclusive hepatitis C antibody test results
+ Assess your response to treatment
PCR viral detection test (Qualitative test)
The PCR viral detection test is mainly used as a confirmatory test when an antibody test result is inconclusive. It is important as you may have received an antibody positive test only to have cleared the virus at a later date. The PCR viral detection test can also be used by HCV positive pregnant women to determine the chance of them transmitting HCV to their child.
PCR viral load test (Quantitative Test)
This PCR lest measures the amount of HCV circulating in someone’s blood. Measuring the level of virus in someone’s blood before treatment can help determine whether a 6 or 12 month treatment regime is preferable.
PCR viral genotype test PCR genotype tests can determine what HCV genotype and subtype a person has. This is useful information as it has been shown that people who have particular genotypes generally respond better to drug treatment Important note: PCR tests look for virus in the blood. Levels of virus in people’s blood can fluctuate and, at times, the level of virus in someone’s blood might be too low for the PCR test to detect it. Therefore, a negative PCR test result may not always mean that a hepatitis C antibody positive person doesn’t have hepatitis C just that the test couldn’t detect the virus in (hat particular sample of blood. For this reason, people should rely on a series of at least two PCR tests done over a 4-6 month period, rather than a single PCR test.
How Can I Tell What’s Happening to my Liver?
Liver function tests (LFTs) (see BP Issue 1) are used to measure the general condition of the liver. Liver function tests measure levels of particular enzymes or proteins in a person’s blood. If liver cells are damaged, increased levels of these substances “leak out” into the bloodstream and show up as raised or abnormal results in liver function tests. The tests provide only a rough indication of possible liver damage. Liver function tests may be suggested monthly or up to once per year depending on a person’s condition. Liver function tests do not provide conclusive evidence of what is happening in the liven some people may feel quite ill yet have little liver damage. For other people, damage may be occurring even when liver enzyme levels arc normal. It is important to remember that raised liver function test results may be caused by medical conditions other than HCV In cases where ALT readings are consistently high for a long time, where they fluctuate greatly or when readings don’t seem to match with how a person feels, a specialist may suggest a liver biopsy be done. Some doctors recommend a routine liver biopsy after 15 years of infection and then every five years thereafter.
What is a Liver Biopsy?
A liver biopsy provides the most accurate report on the condition of someone’s liver. Using a special instrument, a specialist doctor takes a small sample which is then examined under a microscope. Ultrasound and other x-rays can indicate certain liver-related abnormalities but have difficulty distinguishing cirrhosis (scarring of the liver) from other conditions such as fat accumulation in the liver. This is particularly true in early cirrhosis. The diagnosis of cirrhosis can only really be made by liver biopsy. However, the presence or absence of cirrhosis is only part of the information available from liver biopsy. Apart from showing the amount of scar tissue (an indication of what has happened to the liver in the past), liver biopsies also show how active the hepatitis C is now and if there are other factors interacting with the hepatitis C to damage the liver such as excess alcohol or iron accumulation in the liver. (BP will cover biopsy’s in more detail in an upcoming issue).
How Accurate Are Liver Biopsy’s?
A liver biopsy sample is just a tiny piece of the liver and people have said it can be hit and miss depending on the bit of the liver taken, but a properly taken sample is generally representative of changes throughout the liver. Hepatitis C affects the whole liver and although there may be some variation within the liver,this would be a minor, rather than major, variation.A doctor will usually explore two major issues in looking at the liver biopsy: Firstly, are the features consistent with HCV as the cause of the liver test abnormalities? ie. Are there other Ever illnesses present? Secondly, if the biopsy is consistent with HCV, then how badly is the liver damaged? This can be estimated by studying three main parameters:
+ The amount of portal inflammation – this is the inflammation around liver cells, bile ducts and veins in parts of the liver
+ The amount of tabular inflammation – the amount of inflammation in separate lobules (the left, right and smaller subdivisions of the liver)
+ The amount of fibrosis – this is an early stage in the development of liver cell scarring (cirrhosis).
NOTE: Liver biopsies are not used as much in 2011 as they were around 2000 as a more modern, less invasive type of liver ultrasound is preferred.
Is Treatment Successful?
It is important that you develop a partnership with the healthcare professional who will be responsible for your cart. It may be your GP, specialist or alternative healthcare practitioner or better still, a combination of the three. There are some real strides being made in terms of treatment for HCV and treatment outcomes, though variable depending on each individual (lifestyle and viral factors and certain lifestyle changes made can also impact positively on your quality of life). The best course of treatment currently available involves a combination of two drugs; pegylated interferon and ribavirin. Treatment response rates using pegylated alpha interferon plus ribavirin are in the order of 55% (with genotype 1 results of 45%, and genotype 2 and 3 results of about 80%). For the few people unable to tolerate combination therapy, alpha interferon on its own is sometimes beneficial. However, not everyone is considered suitable for treatment Some people need only regular assessment to detect if damage to their liver is occurring or progressing. NB As of 2011, new treatment therapies for HCV are looking much more promising. It is well worth doing a bit of research into what is available through some of the excellent Hep C resources available these days. Treatment can be exhausting and hard work for your body so its important to be prepared and have support.
Discriminated Against for Being HCV+?
If you feel you have been discriminated against because of your status or treated unfairly, there is a group who may be able to advise you on your rights relating to almost any matter that you feel is connected with your hepatitis C.
NOTE: The Disability Rights Commission (DRC) closed on 28 September 2007. Its responsibility for helping secure civil rights for disabled people has transferred to the new Equality and Human Rights Commission which opened for business in 1 October 2007.
Or Call the HEP C Trust (UK) Helpline: 0845 223 4424 10.30 to 4.30 Monday to Fri – people affected by Hep C man the helplines and give good quality information and advice
Thanks to British Liver Trust & The Australian HEP C Council of NSW http://www.hepatitis.org.au/ for their excellent resources and information, some of which is represented here.
Related Articles
■ Scripps Research scientists identify key interaction in hepatitis C virus (scienceblog.com)
■ Hepatitis C – All Information (umm.edu)
■ New Hepatitis C Drugs in the Works (webmd.com)
■ Key interaction in hepatitis C virus identified (sciencedaily.com)
Source
http://www.blackpoppy.org.uk/
Hepatitis C
Once known as Hepatitis Non A Non B, Hepatitis C is being discussed a lot in the using community. Here, BP goes behind the ‘Hep C test’ where many of us stop, discovering why further tests are so important in getting to the bottom of your own Hep C diagnosis.
Research by M.M, B.L, EO
In the last issue, BP ‘introduced’ the liver, briefly discussing what it does and how it does it. This issue, we want to look more closely at a virus that has affected the livers of an estimated 250,000 – 600,000 people in the UK alone, 170 million people worldwide with some 3 million more joining the global ranks each year. BP wanted to find some straightforward answers to some essential questions on Hepatitis C and what you may want to consider if you have been diagnosed Hep C (HCV) positive. (BP will look into treatments for HCV next issue).
Hepatitis C is?…
The actual word “hepatitis’ means inflammation or swelling of the liver. This can be caused by chemicals, drugs, drinking too much alcohol or by different kinds of viruses. Hepatitis C is just one of a number of hepatitis viruses (including A, B,D, E, G) and they are all completely different from one another. It can be hard to get your bead around just how small viruses really are. HCV is estimated to be 80 nanometers in diameter (around 30 billion would fit on this dot {,} – another reason why handwashing before and after injecting is so important; be especially vigilant if someone injects you after they’ve just had a hit – they could have microscopic particles of blood on their fingers and then may place them on your injection site. HCV is known to be remain active outside the body for some time so wash your hands and tell others to wash theirs! The hepatitis C virus is in fact a group of viruses, similar enough to be called HCV virus, yet different enough to be classified into subgroups.
Genotypes
Several families of hepatitis C have been observed around The world and these are known as genotypes, because they differ in their genetic make up. They arc usually classified as HCV genotype 1 ,or 2, or 3, etc. Some genotypes respond better to treatment than others so it is important to identify your genotype when considering treatment for Hep C..
Subtypes
Within each genotype, there are subtypes. These are classified as HCV subtype la, or Ib, Ic, etc and within a subtype, incredibly minute differences will exist among individual viruses, called quasispecies – several million quasispecies would exist within a subtype.
How Might HCV Affect Me?
Hepatitis C affects people differently; some are not affected by it while others can be affected seriously. If you contract hepatitis C, your body will produce antibodies to try and destroy it A HCV lest (referred to as an anti-HCV test) will look for the presence of these antibodies and if found, your result will be HCV antibody positive. However, too many of us stop here, terrified that we now have Hep C. But an antibody positive test is only showing ‘exposure’ to the virus – it does not tell you whether you have ‘active’ virus in the blood. Research shows that of 100 people infected wilh HCV, 25 will clear the virus from their bodies completely with 2-6 months of infection but will continue to carry the antibodies for some time. (These are usually people who were infected when they were younger).
This is why if you have received an HCV antibody positive test, further tests are necessary to determine whether there is still an infection present (see PCR tests opposite) and of course, get yourself some follow up tests for your Hep C, certain discoveries might make all the difference. to help identify the extent of any liver complications or disease – and your suitability for the newer HCV treatments. (BP investigates this next issue). Research estimates the other 75 who do not clear the virus will have ongoing (chronic) infection and some arc at risk of developing complications or liver disease. Of these people, approximately 20 may never experience any noticeable symptoms and although they can still transmit HCV, they won’t develop illness or liver disease.
Symptoms Related to HCV
After 10-15 years, the majority of people with hepatitis C will have developed different levels of liver damage that will result in hepatitis C
Symptoms
These could include;
tiredness and fatigue, headaches, vagueness,
depression, altered sleep patterns, abdominal pain, itches and
rashes, nausea, vomiting
and/or loss of appetite, swelling of the ankles
and/or stomach area, red blotches occurring on the upper body, easy bruising.
Some aspects of the disease are still not fully understood and it can be difficult to predict what will happen for any one person. Symptoms can stay at a certain level and dont always get worse. They can come and go with no real pattern. Over a 40 year period of infection, it is believed that: less than 4% of people with chronic hepatitis C would develop liver failure or liver cancer.. Over a 40 year period, 20% of people with chronic (ongoing) HCV infection will develop cirrhosis of the liver.
I’m Hep C Positive – Now What?
After you receive your antibody positive diagnosis, you can be offered (or request) a referral lo see a specialist. They should then offer you a series of tests such as:
PCR Test, Blood Platelet Count, Liver Function Tests (LFTs), liver Biopsy, Ultrasound or doppler ultrasound, or CT scan
Many doctors advise people with hepatitis C to have the hepatitis A and B vaccinations. Although the viruses are unrelated, such vaccinations will help prevent possible additional liver complications caused by having more than one viral infection at the same time.
What is a PCR Test?
PCR stands for polymerase chain reaction. PCR tests detect or measure the actual hepatitis C virus in a sample of blood There are three types of PCR test – viral detection, viral load and viral genotype. These tests assist people to:
+ Determine whether you may have cleared the virus (but still have antibodies)
+ Determine your level of infectivity
+ Confirm inconclusive hepatitis C antibody test results
+ Assess your response to treatment
PCR viral detection test (Qualitative test)
The PCR viral detection test is mainly used as a confirmatory test when an antibody test result is inconclusive. It is important as you may have received an antibody positive test only to have cleared the virus at a later date. The PCR viral detection test can also be used by HCV positive pregnant women to determine the chance of them transmitting HCV to their child.
PCR viral load test (Quantitative Test)
This PCR lest measures the amount of HCV circulating in someone’s blood. Measuring the level of virus in someone’s blood before treatment can help determine whether a 6 or 12 month treatment regime is preferable.
PCR viral genotype test PCR genotype tests can determine what HCV genotype and subtype a person has. This is useful information as it has been shown that people who have particular genotypes generally respond better to drug treatment Important note: PCR tests look for virus in the blood. Levels of virus in people’s blood can fluctuate and, at times, the level of virus in someone’s blood might be too low for the PCR test to detect it. Therefore, a negative PCR test result may not always mean that a hepatitis C antibody positive person doesn’t have hepatitis C just that the test couldn’t detect the virus in (hat particular sample of blood. For this reason, people should rely on a series of at least two PCR tests done over a 4-6 month period, rather than a single PCR test.
How Can I Tell What’s Happening to my Liver?
Liver function tests (LFTs) (see BP Issue 1) are used to measure the general condition of the liver. Liver function tests measure levels of particular enzymes or proteins in a person’s blood. If liver cells are damaged, increased levels of these substances “leak out” into the bloodstream and show up as raised or abnormal results in liver function tests. The tests provide only a rough indication of possible liver damage. Liver function tests may be suggested monthly or up to once per year depending on a person’s condition. Liver function tests do not provide conclusive evidence of what is happening in the liven some people may feel quite ill yet have little liver damage. For other people, damage may be occurring even when liver enzyme levels arc normal. It is important to remember that raised liver function test results may be caused by medical conditions other than HCV In cases where ALT readings are consistently high for a long time, where they fluctuate greatly or when readings don’t seem to match with how a person feels, a specialist may suggest a liver biopsy be done. Some doctors recommend a routine liver biopsy after 15 years of infection and then every five years thereafter.
What is a Liver Biopsy?
A liver biopsy provides the most accurate report on the condition of someone’s liver. Using a special instrument, a specialist doctor takes a small sample which is then examined under a microscope. Ultrasound and other x-rays can indicate certain liver-related abnormalities but have difficulty distinguishing cirrhosis (scarring of the liver) from other conditions such as fat accumulation in the liver. This is particularly true in early cirrhosis. The diagnosis of cirrhosis can only really be made by liver biopsy. However, the presence or absence of cirrhosis is only part of the information available from liver biopsy. Apart from showing the amount of scar tissue (an indication of what has happened to the liver in the past), liver biopsies also show how active the hepatitis C is now and if there are other factors interacting with the hepatitis C to damage the liver such as excess alcohol or iron accumulation in the liver. (BP will cover biopsy’s in more detail in an upcoming issue).
How Accurate Are Liver Biopsy’s?
A liver biopsy sample is just a tiny piece of the liver and people have said it can be hit and miss depending on the bit of the liver taken, but a properly taken sample is generally representative of changes throughout the liver. Hepatitis C affects the whole liver and although there may be some variation within the liver,this would be a minor, rather than major, variation.A doctor will usually explore two major issues in looking at the liver biopsy: Firstly, are the features consistent with HCV as the cause of the liver test abnormalities? ie. Are there other Ever illnesses present? Secondly, if the biopsy is consistent with HCV, then how badly is the liver damaged? This can be estimated by studying three main parameters:
+ The amount of portal inflammation – this is the inflammation around liver cells, bile ducts and veins in parts of the liver
+ The amount of tabular inflammation – the amount of inflammation in separate lobules (the left, right and smaller subdivisions of the liver)
+ The amount of fibrosis – this is an early stage in the development of liver cell scarring (cirrhosis).
NOTE: Liver biopsies are not used as much in 2011 as they were around 2000 as a more modern, less invasive type of liver ultrasound is preferred.
Is Treatment Successful?
It is important that you develop a partnership with the healthcare professional who will be responsible for your cart. It may be your GP, specialist or alternative healthcare practitioner or better still, a combination of the three. There are some real strides being made in terms of treatment for HCV and treatment outcomes, though variable depending on each individual (lifestyle and viral factors and certain lifestyle changes made can also impact positively on your quality of life). The best course of treatment currently available involves a combination of two drugs; pegylated interferon and ribavirin. Treatment response rates using pegylated alpha interferon plus ribavirin are in the order of 55% (with genotype 1 results of 45%, and genotype 2 and 3 results of about 80%). For the few people unable to tolerate combination therapy, alpha interferon on its own is sometimes beneficial. However, not everyone is considered suitable for treatment Some people need only regular assessment to detect if damage to their liver is occurring or progressing. NB As of 2011, new treatment therapies for HCV are looking much more promising. It is well worth doing a bit of research into what is available through some of the excellent Hep C resources available these days. Treatment can be exhausting and hard work for your body so its important to be prepared and have support.
Discriminated Against for Being HCV+?
If you feel you have been discriminated against because of your status or treated unfairly, there is a group who may be able to advise you on your rights relating to almost any matter that you feel is connected with your hepatitis C.
NOTE: The Disability Rights Commission (DRC) closed on 28 September 2007. Its responsibility for helping secure civil rights for disabled people has transferred to the new Equality and Human Rights Commission which opened for business in 1 October 2007.
Or Call the HEP C Trust (UK) Helpline: 0845 223 4424 10.30 to 4.30 Monday to Fri – people affected by Hep C man the helplines and give good quality information and advice
Thanks to British Liver Trust & The Australian HEP C Council of NSW http://www.hepatitis.org.au/ for their excellent resources and information, some of which is represented here.
Related Articles
■ Scripps Research scientists identify key interaction in hepatitis C virus (scienceblog.com)
■ Hepatitis C – All Information (umm.edu)
■ New Hepatitis C Drugs in the Works (webmd.com)
■ Key interaction in hepatitis C virus identified (sciencedaily.com)
Source
February 4, 2011
Tacere Therapeutics Reacquires Rights to Develop and Commercialize its Hepatitis C Compounds in Asia
SAN JOSE, Calif., Feb. 3, 2011 /PRNewswire/ -- Tacere Therapeutics, Inc., an RNA interference (RNAi)-based therapeutics company, announced today that it has reacquired the development and commercialization rights to its Hepatitis C Virus (HCV) compounds throughout Asia from its strategic partner, Tokyo-based Oncolys BioPharma Inc.
"We are very happy to have regained control of the Asian development and commercialization rights to our family of HCV compounds," said Sara Hall Renison, Chief Executive Officer of Tacere. Mike Catelani, Chairman, President and CFO, added, "With the continued promising development of our lead HCV compound in partnership with Pfizer, holder of the non-Asian worldwide development and commercialization rights, we believe that we are well-positioned to commence regulatory activities in Asia."
About Tacere's family of HCV compounds
Tacere's family of HCV compounds, are novel therapeutic products containing three separate RNAi elements targeted against the Hepatitis C virus itself and encapsidated in an adeno-associated virus (AAV) protein coat. AAV delivery methods have demonstrated clinical safety, and preclinical animal studies with TT-034, the lead compound in the family, have shown the ability to penetrate hepatocytes (the site of HCV replication) at high levels following a single intravenous administration. In preclinical animal studies, this "cocktail in one drug" monotherapy targeted and cleaved the Hepatitis C virus itself at three different sites simultaneously without toxicity.
About Tacere Therapeutics, Inc.
Tacere is an innovative biotechnology company focused on developing therapeutics to treat human diseases using its proprietary knowledge in the development of RNAi therapeutics. Tacere is located in San Jose, California, USA. For additional information, please visit http://www.tacerebio.com/.
CONTACTS
TACERE THERAPEUTICS, INC.
Mike Catelani
Chairman, President & CFO
+1 408 839-1818
info@tacerebio.com
SOURCE Tacere Therapeutics, Inc.
RELATED LINKS
http://www.tacerebio.com/
Source
"We are very happy to have regained control of the Asian development and commercialization rights to our family of HCV compounds," said Sara Hall Renison, Chief Executive Officer of Tacere. Mike Catelani, Chairman, President and CFO, added, "With the continued promising development of our lead HCV compound in partnership with Pfizer, holder of the non-Asian worldwide development and commercialization rights, we believe that we are well-positioned to commence regulatory activities in Asia."
About Tacere's family of HCV compounds
Tacere's family of HCV compounds, are novel therapeutic products containing three separate RNAi elements targeted against the Hepatitis C virus itself and encapsidated in an adeno-associated virus (AAV) protein coat. AAV delivery methods have demonstrated clinical safety, and preclinical animal studies with TT-034, the lead compound in the family, have shown the ability to penetrate hepatocytes (the site of HCV replication) at high levels following a single intravenous administration. In preclinical animal studies, this "cocktail in one drug" monotherapy targeted and cleaved the Hepatitis C virus itself at three different sites simultaneously without toxicity.
About Tacere Therapeutics, Inc.
Tacere is an innovative biotechnology company focused on developing therapeutics to treat human diseases using its proprietary knowledge in the development of RNAi therapeutics. Tacere is located in San Jose, California, USA. For additional information, please visit http://www.tacerebio.com/.
CONTACTS
TACERE THERAPEUTICS, INC.
Mike Catelani
Chairman, President & CFO
+1 408 839-1818
info@tacerebio.com
SOURCE Tacere Therapeutics, Inc.
RELATED LINKS
http://www.tacerebio.com/
Source
Study shows cytokines lymphotoxin can lead to liver cancer
Thursday, February 03, 2011 1:21 PM
VIENNA, Feb. 3, 2011 (Xinhua News Agency) -- Austrian scientist Johannes Haybaeck discovered that increased levels of cytokines lymphotoxin could cause liver infection and develops to liver cancer later. The findings made him win the Pfizer (NYSE:PFE) Research Awards 2011 presented by Medical University Graz, Austria, on Thursday.
Accordingly, a high-level concentration of cytokines lymphotoxin (LT) alpha and beta and their receptor LT beta R can be found in the liver tissue of patients infected with hepatitis B- or hepatitis C virus.
The lymphotoxin ultimately led to a liver infection that developed to liver cancer later. In addition, the altered liver cells form metastases that spread within the liver.
In addition to chronic alcohol abuse, drug abuse or fungal toxins, virus infection was believed to be one of the most common causes of liver inflammation and liver cancer.
The scientists obtained the results by conducting tumor therapies in mice. They produced a lot of LTs to the liver tissues of the mice though a genetic material change and finally came to the experimental results.
Whether the observations in the mice can also play a role in the human liver tumor cells is still unclear. Hayb?ck and his research colleagues are underway.
(Source: )
(Source: Quotemedia)
Source
VIENNA, Feb. 3, 2011 (Xinhua News Agency) -- Austrian scientist Johannes Haybaeck discovered that increased levels of cytokines lymphotoxin could cause liver infection and develops to liver cancer later. The findings made him win the Pfizer (NYSE:PFE) Research Awards 2011 presented by Medical University Graz, Austria, on Thursday.
Accordingly, a high-level concentration of cytokines lymphotoxin (LT) alpha and beta and their receptor LT beta R can be found in the liver tissue of patients infected with hepatitis B- or hepatitis C virus.
The lymphotoxin ultimately led to a liver infection that developed to liver cancer later. In addition, the altered liver cells form metastases that spread within the liver.
In addition to chronic alcohol abuse, drug abuse or fungal toxins, virus infection was believed to be one of the most common causes of liver inflammation and liver cancer.
The scientists obtained the results by conducting tumor therapies in mice. They produced a lot of LTs to the liver tissues of the mice though a genetic material change and finally came to the experimental results.
Whether the observations in the mice can also play a role in the human liver tumor cells is still unclear. Hayb?ck and his research colleagues are underway.
(Source: )
(Source: Quotemedia)
Source
Hepatitis C remains prominent among injection drug users
Updated: 2011-02-02 14:19:52 CST
While injection drug users may be contracting HIV at lower rates than they did two decades ago, they are receiving positive hepatitis C tests just as frequently as ever. These are the findings of a new study published in the Journal of Infectious Disease.
The Johns Hopkins University researchers who led the study said that the findings show that efforts to curb the spread of blood-borne diseases are showing some positive results. However, they said that more needs to be done to combat the dangerous spread of hepatitis C.
For the study, the researchers looked at infection rates among injection drug users of both HIV and hepatitis C, or HCV, dating back to 1988. While the numbers showed a significant decline in HIV cases, HCV infections remained more constant.
Given the fact that these infections generally spread from injection drug users into the general population, the researchers said that it is important to institute more effective programs for preventing the spread of infection, such as needle exchange programs.
"Current prevention efforts delay but do not prevent HCV at the population level and will need to be further intensified to reduce risk of HCV infection to the level of HIV," the researchers said
Astex Therapeutics Receives Milestone from Wellcome Trust for Pioneering HCV Research
2011-02-01, Source: Astex Therapeutics
Astex Therapeutics, the UK-based biotechnology company developing targeted therapies for oncology and virology, announced that it has received a milestone payment of £1 million from the Wellcome Trust to support the Company's pioneering work in the area of infectious disease caused by Hepatitis C Virus (HCV). The payment is the second installment of an award of £2 million made by Wellcome to Astex in 2009 under its ''Seeding Drug Discovery" initiative.
The milestone payment was triggered by the identification of potent, small molecule inhibitors of HCV NS3 - a key protein involved in viral replication. The compounds act as allosteric modulators of the NS3 protein resulting in inhibition of the enzyme activities of both protease and helicase in wild type and in drug resistant variants of HCV that have arisen in the clinic during treatment with active site inhibitors. As such the Astex compounds offer the potential to be differentiated from existing HCV protease inhibitors. Astex retains all commercial rights to the resulting drug candidates from this programme. Harren Jhoti, Chief Executive Officer of Astex said, "We anticipate that targeted agents like these will provide new therapeutic options for patients with HCV infections where current treatments are not optimal and where resistance to current treatments is a recurring problem."
Contact
Jeremy Carmichael, PhD Director of Business Development Astex Therapeutics Ltd 436 Cambridge Science Park Milton Road, Cambridge CB4 0QA, UK Tel: +44(0)1223 226200 Fax: +44(0)1223 226201 j.carmichael@astex-therapeutics.com http://www.astex-therapeutics.com/
About Astex Therapeutics
Astex is a UK-based biotechnology company that discovers and develops novel small molecule therapeutics. Using its pioneering fragment-based drug discovery platform Pyramid(TM), Astex has built a pipeline of molecularly-targeted oncology drugs, of which three are currently being tested in clinical trials with others in discovery and pre-clinical development. In addition to its proprietary research programmes, Astex's productivity in lead discovery has been endorsed through numerous partnerships with major pharmaceutical companies, including AstraZeneca, GlaxoSmithKline, Johnson and Johnson and Novartis.
For further information on Astex please visit the Company's website at http://www.astex-therapeutics.com/
About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. http://www.wellcome.ac.uk/
Source
Astex Therapeutics, the UK-based biotechnology company developing targeted therapies for oncology and virology, announced that it has received a milestone payment of £1 million from the Wellcome Trust to support the Company's pioneering work in the area of infectious disease caused by Hepatitis C Virus (HCV). The payment is the second installment of an award of £2 million made by Wellcome to Astex in 2009 under its ''Seeding Drug Discovery" initiative.
The milestone payment was triggered by the identification of potent, small molecule inhibitors of HCV NS3 - a key protein involved in viral replication. The compounds act as allosteric modulators of the NS3 protein resulting in inhibition of the enzyme activities of both protease and helicase in wild type and in drug resistant variants of HCV that have arisen in the clinic during treatment with active site inhibitors. As such the Astex compounds offer the potential to be differentiated from existing HCV protease inhibitors. Astex retains all commercial rights to the resulting drug candidates from this programme. Harren Jhoti, Chief Executive Officer of Astex said, "We anticipate that targeted agents like these will provide new therapeutic options for patients with HCV infections where current treatments are not optimal and where resistance to current treatments is a recurring problem."
Contact
Jeremy Carmichael, PhD Director of Business Development Astex Therapeutics Ltd 436 Cambridge Science Park Milton Road, Cambridge CB4 0QA, UK Tel: +44(0)1223 226200 Fax: +44(0)1223 226201 j.carmichael@astex-therapeutics.com http://www.astex-therapeutics.com/
About Astex Therapeutics
Astex is a UK-based biotechnology company that discovers and develops novel small molecule therapeutics. Using its pioneering fragment-based drug discovery platform Pyramid(TM), Astex has built a pipeline of molecularly-targeted oncology drugs, of which three are currently being tested in clinical trials with others in discovery and pre-clinical development. In addition to its proprietary research programmes, Astex's productivity in lead discovery has been endorsed through numerous partnerships with major pharmaceutical companies, including AstraZeneca, GlaxoSmithKline, Johnson and Johnson and Novartis.
For further information on Astex please visit the Company's website at http://www.astex-therapeutics.com/
About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. http://www.wellcome.ac.uk/
Source
Vertex Urges CDC to Recommend Hep C Screening, To Nudge “Second Tsunami” of Patients
Luke Timmerman 2/2/11
If Vertex Pharmaceuticals gets its way in talks with U.S. public health officials, most people over 50 could soon get blood tests to screen for hepatitis C infections at the doctor’s office. If the U.S. Centers for Disease Control and Prevention (CDC) agrees this is a good idea, it could prompt another 1 million patients who don’t realize they are infected to come out of the woodwork and start clamoring for Vertex’s new hepatitis C drug over the next few years.
The Cambridge, MA-based biotech company (NASDAQ: VRTX), which has operations in San Diego, has joined other drugmakers in supporting studies they hope will persuade the CDC to recommend routine screening for hepatitis C, Vertex CEO Matt Emmens said in a recent interview. The company is one of the sponsors of what’s called the Viral Hepatitis Action Coalition, a public-private partnership with the CDC, which is conducting studies known as BEST-C. These studies could determine how effective it is to screen patients for hepatitis C infection more widely.
These studies, which are expected to cost a total of $3.6 million, could be worth billions to Vertex if they show that screening random Baby Boomers is worthwhile.
An estimated 600,000 patients in the U.S. are expected to seek treatment that could include Vertex’s drug, or a rival offering from Merck, if the FDA clears the new drugs for sale as analysts expect in the middle of this year. The two new protease inhibitors are being hailed as major steps forward, as they have been shown to roughly double cure rates of hepatitis C, a viral infection that damages the liver over many years. Vertex’s drug, telaprevir, has shown it can push the cure rate up as high as about 75 percent, while cutting the treatment time in half to about six months. That means patients don’t have to endure such a long period of flu-like symptoms, which has traditionally discouraged many patients from getting treatment.
The new advance from Vertex, demonstrated in a trio of pivotal clinical trials, has created this huge wave of pent-up demand from patients and doctors. Knowing this, many analysts have projected the product will be pretty much an instant hit, topping $2 billion in U.S. sales after just a couple years. But then, some expect sales to taper off, as many of the most motivated patients get cured, and don’t need the drug anymore. Essentially, they see Vertex possibly becoming a victim of its own success.
That’s not how it will play out, says Emmens, a marketing veteran who spent much of his career at Merck. An estimated 3.2 million to 3.9 million people in the U.S. have chronic hepatitis C infections. That’s a lot more than the initial wave of patients, which is mostly composed of people who sought treatment before but relapsed. Besides those patients, many more candidates are Baby Boomers who don’t know they contracted the hepatitis C infection decades ago through unprotected sex, IV drug use, or blood transfusions from contaminated supplies. Many of these infections lie dormant for about 20 years or more, but are just now starting to emerge over the decade to come, Emmens says. Some patients won’t see symptoms at all, and as the AP pointed out in this solid feature last month, it’s hard to tell which infected patients are likely to get the worst symptoms. The unluckiest ones will end up suffering severe liver scarring (cirrhosis), liver cancer, liver transplants, and ultimately, premature death.
Connecting with that massive crowd of patients, who aren’t motivated to seek treatment today because they don’t see any really bad symptoms yet, is one of the big marketing challenges Vertex faces. The company is planning to spend some of its $1.3 billion cash hoard on a public awareness campaign designed to urge people to get tested to see if they have the virus, Emmens says. But even more important than the ad campaign, Vertex is hoping the CDC will recommend routine hepatitis C screening, which would start turning up a lot more positive tests. If it does, Emmens he predicts it could prompt another 1 million patients to seek treat treatment around 2014 and later, right as the most people in the initial wave of highly motivated patients go home having been cured.
“You have an estimated 2 million people out there who are not aware they are infected,” Emmens says. “Some don’t know, or just don’t give a damn, or have other problems, and won’t seek treatment. But if you found 1 million new patients over a two or three-year period, there’s a second tsunami.”
As for analysts predicting telaprevir will rise and fall, Emmens shook his head. “That’s absurd. I understand they’ve got to do their job. But from a marketing guy’s perspective, that just doesn’t happen unless you lose your patent,” Emmens says. “Docs use what works. Patients will come in, and they will want the highest chance they can get of a cure. That’s what they really care about.” A shorter treatment period, and more convenient twice-daily dosing instead of thrice-daily are a couple of other features Vertex is hoping to incorporate into hepatitis C treatment, he adds.
Vertex has clearly been spending a lot of time lately thinking about making its case to insurers. The trick will be to persuade insurers that it’s worth spending quite a bit of money upfront on a potent new drug to attack a dormant infection, as opposed to waiting to see if patients get sick years later and rack up big hospital bills. Emmens notes that liver transplants cost around $300,000, and, obviously, not everyone who wants a new liver actually survives long enough to get to the top of the waiting list. Vertex, citing an actuarial study it sponsored to try to measure the cost of future treatment, says medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion—presumably when factoring in a lot of liver transplants.
I must say I’m personally wary of drugmakers who use their money and influence to rewrite health guidelines that end up favoring their bottom line. Companies that want to sell more drugs for high blood pressure, osteoporosis, and obesity have been known to push for new health guidelines that classify many more people as “Suddenly Sick” as a couple of my former Seattle Times colleagues wrote in a terrific investigative story in 2005. Whether this aggressive new treatment is really beneficial to people’s health over the long run is often unknown.
This case strikes me as somewhat different, though, because today’s available hepatitis C treatment is really so poor. Vertex and Merck are essentially coming along with drugs that represent a big leap ahead with potential to cure hundreds of thousands, maybe millions, of people. It will probably cost taxpayers a few billion dollars a year for many years to come, and it’s always hard to say for sure how many billions you might save down the road when people don’t end up in the hospital getting liver transplants. But you can be sure Vertex is working hard behind the scenes right now to convince officials that an ounce of prevention is worth a pound of cure.
Luke Timmerman is the National Biotech Editor of Xconomy, and the Editor of Xconomy Seattle. You can e-mail him at ltimmerman@xconomy.com, or follow him at twitter.com/ldtimmerman.
Source
If Vertex Pharmaceuticals gets its way in talks with U.S. public health officials, most people over 50 could soon get blood tests to screen for hepatitis C infections at the doctor’s office. If the U.S. Centers for Disease Control and Prevention (CDC) agrees this is a good idea, it could prompt another 1 million patients who don’t realize they are infected to come out of the woodwork and start clamoring for Vertex’s new hepatitis C drug over the next few years.
The Cambridge, MA-based biotech company (NASDAQ: VRTX), which has operations in San Diego, has joined other drugmakers in supporting studies they hope will persuade the CDC to recommend routine screening for hepatitis C, Vertex CEO Matt Emmens said in a recent interview. The company is one of the sponsors of what’s called the Viral Hepatitis Action Coalition, a public-private partnership with the CDC, which is conducting studies known as BEST-C. These studies could determine how effective it is to screen patients for hepatitis C infection more widely.
These studies, which are expected to cost a total of $3.6 million, could be worth billions to Vertex if they show that screening random Baby Boomers is worthwhile.
An estimated 600,000 patients in the U.S. are expected to seek treatment that could include Vertex’s drug, or a rival offering from Merck, if the FDA clears the new drugs for sale as analysts expect in the middle of this year. The two new protease inhibitors are being hailed as major steps forward, as they have been shown to roughly double cure rates of hepatitis C, a viral infection that damages the liver over many years. Vertex’s drug, telaprevir, has shown it can push the cure rate up as high as about 75 percent, while cutting the treatment time in half to about six months. That means patients don’t have to endure such a long period of flu-like symptoms, which has traditionally discouraged many patients from getting treatment.
The new advance from Vertex, demonstrated in a trio of pivotal clinical trials, has created this huge wave of pent-up demand from patients and doctors. Knowing this, many analysts have projected the product will be pretty much an instant hit, topping $2 billion in U.S. sales after just a couple years. But then, some expect sales to taper off, as many of the most motivated patients get cured, and don’t need the drug anymore. Essentially, they see Vertex possibly becoming a victim of its own success.
That’s not how it will play out, says Emmens, a marketing veteran who spent much of his career at Merck. An estimated 3.2 million to 3.9 million people in the U.S. have chronic hepatitis C infections. That’s a lot more than the initial wave of patients, which is mostly composed of people who sought treatment before but relapsed. Besides those patients, many more candidates are Baby Boomers who don’t know they contracted the hepatitis C infection decades ago through unprotected sex, IV drug use, or blood transfusions from contaminated supplies. Many of these infections lie dormant for about 20 years or more, but are just now starting to emerge over the decade to come, Emmens says. Some patients won’t see symptoms at all, and as the AP pointed out in this solid feature last month, it’s hard to tell which infected patients are likely to get the worst symptoms. The unluckiest ones will end up suffering severe liver scarring (cirrhosis), liver cancer, liver transplants, and ultimately, premature death.
Connecting with that massive crowd of patients, who aren’t motivated to seek treatment today because they don’t see any really bad symptoms yet, is one of the big marketing challenges Vertex faces. The company is planning to spend some of its $1.3 billion cash hoard on a public awareness campaign designed to urge people to get tested to see if they have the virus, Emmens says. But even more important than the ad campaign, Vertex is hoping the CDC will recommend routine hepatitis C screening, which would start turning up a lot more positive tests. If it does, Emmens he predicts it could prompt another 1 million patients to seek treat treatment around 2014 and later, right as the most people in the initial wave of highly motivated patients go home having been cured.
“You have an estimated 2 million people out there who are not aware they are infected,” Emmens says. “Some don’t know, or just don’t give a damn, or have other problems, and won’t seek treatment. But if you found 1 million new patients over a two or three-year period, there’s a second tsunami.”
As for analysts predicting telaprevir will rise and fall, Emmens shook his head. “That’s absurd. I understand they’ve got to do their job. But from a marketing guy’s perspective, that just doesn’t happen unless you lose your patent,” Emmens says. “Docs use what works. Patients will come in, and they will want the highest chance they can get of a cure. That’s what they really care about.” A shorter treatment period, and more convenient twice-daily dosing instead of thrice-daily are a couple of other features Vertex is hoping to incorporate into hepatitis C treatment, he adds.
Vertex has clearly been spending a lot of time lately thinking about making its case to insurers. The trick will be to persuade insurers that it’s worth spending quite a bit of money upfront on a potent new drug to attack a dormant infection, as opposed to waiting to see if patients get sick years later and rack up big hospital bills. Emmens notes that liver transplants cost around $300,000, and, obviously, not everyone who wants a new liver actually survives long enough to get to the top of the waiting list. Vertex, citing an actuarial study it sponsored to try to measure the cost of future treatment, says medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion—presumably when factoring in a lot of liver transplants.
I must say I’m personally wary of drugmakers who use their money and influence to rewrite health guidelines that end up favoring their bottom line. Companies that want to sell more drugs for high blood pressure, osteoporosis, and obesity have been known to push for new health guidelines that classify many more people as “Suddenly Sick” as a couple of my former Seattle Times colleagues wrote in a terrific investigative story in 2005. Whether this aggressive new treatment is really beneficial to people’s health over the long run is often unknown.
This case strikes me as somewhat different, though, because today’s available hepatitis C treatment is really so poor. Vertex and Merck are essentially coming along with drugs that represent a big leap ahead with potential to cure hundreds of thousands, maybe millions, of people. It will probably cost taxpayers a few billion dollars a year for many years to come, and it’s always hard to say for sure how many billions you might save down the road when people don’t end up in the hospital getting liver transplants. But you can be sure Vertex is working hard behind the scenes right now to convince officials that an ounce of prevention is worth a pound of cure.
Luke Timmerman is the National Biotech Editor of Xconomy, and the Editor of Xconomy Seattle. You can e-mail him at ltimmerman@xconomy.com, or follow him at twitter.com/ldtimmerman.
Source
January 31, 2011
Quantitation of pretreatment serum interferon-γ-inducible protein-10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response
Hepatology. 2011 Jan;53(1):14-22. doi: 10.1002/hep.24056.
Darling JM, Aerssens J, Fanning G, McHutchison JG, Goldstein DB, Thompson AJ, Shianna KV, Afdhal NH, Hudson ML, Howell CD, Talloen W, Bollekens J, De Wit M, Scholliers A, Fried MW.
University of North Carolina, Chapel Hill, NC.
Abstract
Polymorphisms of the IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of interferon-γ-inducible protein-10 (IP-10) may also differentiate antiviral response. We evaluated IP-10 levels in pretreatment serum from 115 nonresponders and 157 sustained responders in the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African American (AA) and Caucasian American (CA) patients. Mean IP-10 was lower in sustained responders compared with nonresponders (437 ± 31 vs 704 ± 44 pg/mL, P < 0.001), both in AA and CA patients. The positive predictive value of low IP-10 levels (<600 pg/mL) for SVR was 69%, whereas the negative predictive value of high IP-10 levels (>600 pg/mL) was 67%. We assessed the combination of pretreatment IP-10 levels with IL28B genotype as predictors of treatment response. The IL28B polymorphism rs12979860 was tested in 210 participants. The CC, CT, and TT genotypes were found in 30%, 49%, and 21% of patients, respectively, with corresponding SVR rates of 87%, 50%, and 39% (P < 0.0001). Serum IP-10 levels within the IL28B genotype groups provided additional information regarding the likelihood of SVR (P < 0.0001). CT carriers with low IP-10 had 64% SVR versus 24% with high IP-10. Similarly, a higher SVR rate was identified for TT and CC carriers with low versus high IP-10 (TT, 48% versus 20%; CC, 89% versus 79%). IL28B genotype and baseline IP-10 levels were additive but independent when predicting SVR in both AA and CA patients. Conclusion: When IL28B genotype is combined with pretreatment serum IP-10 measurement, the predictive value for discrimination between SVR and nonresponse is significantly improved, especially in non-CC genotypes. This relationship warrants further investigation to elucidate the mechanisms of antiviral response and prospective validation. (Hepatology 2011;).
Copyright © 2010 American Association for the Study of Liver Diseases.
PMID: 21254158 [PubMed - in process]
Source
Darling JM, Aerssens J, Fanning G, McHutchison JG, Goldstein DB, Thompson AJ, Shianna KV, Afdhal NH, Hudson ML, Howell CD, Talloen W, Bollekens J, De Wit M, Scholliers A, Fried MW.
University of North Carolina, Chapel Hill, NC.
Abstract
Polymorphisms of the IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of interferon-γ-inducible protein-10 (IP-10) may also differentiate antiviral response. We evaluated IP-10 levels in pretreatment serum from 115 nonresponders and 157 sustained responders in the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African American (AA) and Caucasian American (CA) patients. Mean IP-10 was lower in sustained responders compared with nonresponders (437 ± 31 vs 704 ± 44 pg/mL, P < 0.001), both in AA and CA patients. The positive predictive value of low IP-10 levels (<600 pg/mL) for SVR was 69%, whereas the negative predictive value of high IP-10 levels (>600 pg/mL) was 67%. We assessed the combination of pretreatment IP-10 levels with IL28B genotype as predictors of treatment response. The IL28B polymorphism rs12979860 was tested in 210 participants. The CC, CT, and TT genotypes were found in 30%, 49%, and 21% of patients, respectively, with corresponding SVR rates of 87%, 50%, and 39% (P < 0.0001). Serum IP-10 levels within the IL28B genotype groups provided additional information regarding the likelihood of SVR (P < 0.0001). CT carriers with low IP-10 had 64% SVR versus 24% with high IP-10. Similarly, a higher SVR rate was identified for TT and CC carriers with low versus high IP-10 (TT, 48% versus 20%; CC, 89% versus 79%). IL28B genotype and baseline IP-10 levels were additive but independent when predicting SVR in both AA and CA patients. Conclusion: When IL28B genotype is combined with pretreatment serum IP-10 measurement, the predictive value for discrimination between SVR and nonresponse is significantly improved, especially in non-CC genotypes. This relationship warrants further investigation to elucidate the mechanisms of antiviral response and prospective validation. (Hepatology 2011;).
Copyright © 2010 American Association for the Study of Liver Diseases.
PMID: 21254158 [PubMed - in process]
Source
Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection
Hepatology. 2011 Jan;53(1):317-24. doi: 10.1002/hep.24074.
Charlton MR, Thompson A, Veldt BJ, Watt K, Tillmann H, Poterucha JJ, Heimbach JK, Goldstein D, McHutchison J.
Division of Gastroenterology and Hepatology and. charlton.michael@mayo.edu
Abstract
Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related). Conclusion: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection. (Hepatology 2011;).
Copyright © 2010 American Association for the Study of Liver Diseases.
Source
Charlton MR, Thompson A, Veldt BJ, Watt K, Tillmann H, Poterucha JJ, Heimbach JK, Goldstein D, McHutchison J.
Division of Gastroenterology and Hepatology and. charlton.michael@mayo.edu
Abstract
Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related). Conclusion: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection. (Hepatology 2011;).
Copyright © 2010 American Association for the Study of Liver Diseases.
Source
Impact of hepatitis C virus infection on the course and outcome of patients with acute alcoholic hepatitis
Eur J Gastroenterol Hepatol. 2011 Jan 20. [Epub ahead of print]
Singal AK, Sagi S, Kuo YF, Weinman S.
aDepartment of Internal Medicine, Division of Gastroenterology bDepartment of Internal Medicine cBiostatististics, Center for Aging, University of Texas Medical Branch, Galveston, Texas dLiver Center and Department of Internal Medicine, University of Kansas, Kansas City, Kansas, USA.
Abstract
BACKGROUND AND AIMS: Limited information is available on the impact of hepatitis C virus (HCV) infection on the clinical course and outcome of acute alcoholic hepatitis (AH), a condition with a significant mortality. We designed this retrospective study to assess effect of HCV on the outcome of patients with AH.
METHODS: Medical charts of patients with a discharge diagnosis of AH (defined using rigorous clinical criteria) were reviewed. Patients were stratified based on the presence or absence of concomitant HCV infection. The disease severity was estimated at admission and at day 7 using model for end-stage disease and discriminant function index scores. Patient survival at 6 months was confirmed with the county death registry. RESULTS : A total of 76 (29 HCV positive) AH cases were analyzed. At admission, disease severity was similar in both groups with severe disease in 53% (49% of AH alone and 59% of AH+HCV; P=0.18). Although severity scores at day 7 were not available for all patients, disease severity tended to be worse for patients with AH+HCV. Kaplan-Meier survival curves showed a poor survival for AH+HCV compared with AH alone (69 vs. 91%; log-rank P=0.015). Although patients with AH+HCV were treated less often compared with AH alone (27 vs. 54%; P=0.05), HCV emerged as an independent risk factor for a poor outcome at 6 months (Cox proportional hazard ratio 8.45; P=0.01) after controlling for patient demographics, disease severity at admission, and treatment.
CONCLUSION: HCV may be a risk factor for patients with AH with a worse outcome at 6 months. If our findings are confirmed in larger databases, prospective studies are needed to examine mechanisms for this effect of HCV on the outcome of AH.
PMID: 21258239 [PubMed - as supplied by publisher]
Source
Singal AK, Sagi S, Kuo YF, Weinman S.
aDepartment of Internal Medicine, Division of Gastroenterology bDepartment of Internal Medicine cBiostatististics, Center for Aging, University of Texas Medical Branch, Galveston, Texas dLiver Center and Department of Internal Medicine, University of Kansas, Kansas City, Kansas, USA.
Abstract
BACKGROUND AND AIMS: Limited information is available on the impact of hepatitis C virus (HCV) infection on the clinical course and outcome of acute alcoholic hepatitis (AH), a condition with a significant mortality. We designed this retrospective study to assess effect of HCV on the outcome of patients with AH.
METHODS: Medical charts of patients with a discharge diagnosis of AH (defined using rigorous clinical criteria) were reviewed. Patients were stratified based on the presence or absence of concomitant HCV infection. The disease severity was estimated at admission and at day 7 using model for end-stage disease and discriminant function index scores. Patient survival at 6 months was confirmed with the county death registry. RESULTS : A total of 76 (29 HCV positive) AH cases were analyzed. At admission, disease severity was similar in both groups with severe disease in 53% (49% of AH alone and 59% of AH+HCV; P=0.18). Although severity scores at day 7 were not available for all patients, disease severity tended to be worse for patients with AH+HCV. Kaplan-Meier survival curves showed a poor survival for AH+HCV compared with AH alone (69 vs. 91%; log-rank P=0.015). Although patients with AH+HCV were treated less often compared with AH alone (27 vs. 54%; P=0.05), HCV emerged as an independent risk factor for a poor outcome at 6 months (Cox proportional hazard ratio 8.45; P=0.01) after controlling for patient demographics, disease severity at admission, and treatment.
CONCLUSION: HCV may be a risk factor for patients with AH with a worse outcome at 6 months. If our findings are confirmed in larger databases, prospective studies are needed to examine mechanisms for this effect of HCV on the outcome of AH.
PMID: 21258239 [PubMed - as supplied by publisher]
Source
Study finds little decline in hepatitis C infections among injection drug users
Public release date: 31-Jan-2011
Contact: John Heys
jheys@idsociety.org
703-299-0412
Infectious Diseases Society of America
Research suggests improvements in prevention and treatment efforts needed
[EMBARGOED FOR JAN. 31, 2011] A recent 20-year study of injection drug users (IDUs) in Baltimore found a significant decline in new cases of HIV infection but only a slight decline in new cases of hepatitis C virus (HCV) infection. The findings suggest that efforts to curb blood-borne transmission of these viral infections have had success but must be expanded against the highly transmissible HCV. Researchers from Johns Hopkins School of Public Health and other centers, led by Shruti H. Mehta, PhD, MPH, report the findings in the March 1 issue of The Journal of Infectious Diseases, now available online. (Please see below for a link to the embargoed study online.)
Previous data had suggested that HIV incidence among IDUs has declined. This trend is often attributed in part to harm reduction measures, including needle exchange programs and substance abuse treatment. However, these measures have not been as successful in lowering the rates of HCV incidence and prevalence. For example, HCV infection is nearly 10 times more transmissible by sharing needles than is HIV infection. Sharing a needle even once can be enough to transmit HCV.
The investigators found that new cases of HIV infection declined dramatically across four different time periods during the past 20 years, from 5.5 per 100 person-years (PY) in 1988-'89, to two per 100 PY in 1994-'95, and to zero cases in 1998 and 2005-'08. While researchers also observed reductions in new cases of HCV infection, these were not nearly as substantial: from 22 per 100 PY in 1988-'89, to 17.2 per 100 PY in 1994-'95, to 17.9 in 1998, and to 7.8 per 100 PY in 2005-'08. Overall, cases appeared to decline only among younger IDUs, who had started injecting drugs recently.
According to researchers, these data suggest that "current prevention efforts delay but do not prevent HCV at the population level and will need to be further intensified to reduce risk of HCV infection to the level of HIV." Efforts on both the prevention and the treatment fronts to reduce the reservoir of HCV-infected IDUs will have to be expanded, the investigators concluded.
In an accompanying editorial, Jason Grebeley, PhD, and Gregory J. Dore, MB BS, MPH, PhD, of the University of New South Wales in Australia, agreed that higher prevalence of HCV infection and greater transmission risk following an injection with a contaminated syringe as compared to HIV have hampered harm reduction measures. They also noted that current implementation of harm reduction measures in most settings is inadequate. Rates of equipment sharing remain high, and access to opioid substitution therapy and other drug treatment programs is limited.
The editorial authors also pointed out the impact that an HCV vaccine could have on new cases of HCV infection. Though a highly efficacious vaccine has not yet been discovered, efforts to do so are crucial. They suggested that even though the window for preventing HCV may be small, improvements in HCV prevention are feasible.
###
Fast Facts:
1) Among the community of injection drug users (IDUs) in Baltimore, HIV incidence declined dramatically over 20 years, while new cases of hepatitis C virus (HCV) infection declined only slightly.
2) HIV incidence decreased from 5.5 per 100 person-years (PY) in 1988-'89, to two per 100 PY in 1994-'95, and to zero in 1998 and 2005-'08. The declines in HCV infection were not nearly as substantial: from 22 per 100 PY in 1988-'89, to 17.2 per 100 PY in 1994-'95, to 17.9 in 1998, and to 7.8 per 100 PY in 2005-'08.
3) Prevention and treatment efforts must be expanded to reduce the number of HCV infections among IDUs.
NOTE: The study and the accompanying editorial are available online. They are embargoed until 12:01 a.m. EST on Monday, Jan. 31, 2011:
"Changes in Blood-borne Infection Risk Among Injection Drug Users" http://www.oxfordjournals.org/our_journals/jid/jiq112.pdf
"Prevention of Hepatitis C Virus in Injecting Drug Users: A Narrow Window of Opportunity" http://www.oxfordjournals.org/our_journals/jid/jiq111.pdf
Founded in 1904, The Journal of Infectious Diseases is the premier publication in the Western Hemisphere for original research on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune mechanisms. Articles in JID include research results from microbiology, immunology, epidemiology, and related disciplines. JID is published under the auspices of the Infectious Diseases Society of America (IDSA). Based in Arlington, Va., IDSA is a professional society representing more than 9,000 physicians and scientists who specialize in infectious diseases. For more information, visit http://www.idsociety.org/.
Source
Contact: John Heys
jheys@idsociety.org
703-299-0412
Infectious Diseases Society of America
Research suggests improvements in prevention and treatment efforts needed
[EMBARGOED FOR JAN. 31, 2011] A recent 20-year study of injection drug users (IDUs) in Baltimore found a significant decline in new cases of HIV infection but only a slight decline in new cases of hepatitis C virus (HCV) infection. The findings suggest that efforts to curb blood-borne transmission of these viral infections have had success but must be expanded against the highly transmissible HCV. Researchers from Johns Hopkins School of Public Health and other centers, led by Shruti H. Mehta, PhD, MPH, report the findings in the March 1 issue of The Journal of Infectious Diseases, now available online. (Please see below for a link to the embargoed study online.)
Previous data had suggested that HIV incidence among IDUs has declined. This trend is often attributed in part to harm reduction measures, including needle exchange programs and substance abuse treatment. However, these measures have not been as successful in lowering the rates of HCV incidence and prevalence. For example, HCV infection is nearly 10 times more transmissible by sharing needles than is HIV infection. Sharing a needle even once can be enough to transmit HCV.
The investigators found that new cases of HIV infection declined dramatically across four different time periods during the past 20 years, from 5.5 per 100 person-years (PY) in 1988-'89, to two per 100 PY in 1994-'95, and to zero cases in 1998 and 2005-'08. While researchers also observed reductions in new cases of HCV infection, these were not nearly as substantial: from 22 per 100 PY in 1988-'89, to 17.2 per 100 PY in 1994-'95, to 17.9 in 1998, and to 7.8 per 100 PY in 2005-'08. Overall, cases appeared to decline only among younger IDUs, who had started injecting drugs recently.
According to researchers, these data suggest that "current prevention efforts delay but do not prevent HCV at the population level and will need to be further intensified to reduce risk of HCV infection to the level of HIV." Efforts on both the prevention and the treatment fronts to reduce the reservoir of HCV-infected IDUs will have to be expanded, the investigators concluded.
In an accompanying editorial, Jason Grebeley, PhD, and Gregory J. Dore, MB BS, MPH, PhD, of the University of New South Wales in Australia, agreed that higher prevalence of HCV infection and greater transmission risk following an injection with a contaminated syringe as compared to HIV have hampered harm reduction measures. They also noted that current implementation of harm reduction measures in most settings is inadequate. Rates of equipment sharing remain high, and access to opioid substitution therapy and other drug treatment programs is limited.
The editorial authors also pointed out the impact that an HCV vaccine could have on new cases of HCV infection. Though a highly efficacious vaccine has not yet been discovered, efforts to do so are crucial. They suggested that even though the window for preventing HCV may be small, improvements in HCV prevention are feasible.
###
Fast Facts:
1) Among the community of injection drug users (IDUs) in Baltimore, HIV incidence declined dramatically over 20 years, while new cases of hepatitis C virus (HCV) infection declined only slightly.
2) HIV incidence decreased from 5.5 per 100 person-years (PY) in 1988-'89, to two per 100 PY in 1994-'95, and to zero in 1998 and 2005-'08. The declines in HCV infection were not nearly as substantial: from 22 per 100 PY in 1988-'89, to 17.2 per 100 PY in 1994-'95, to 17.9 in 1998, and to 7.8 per 100 PY in 2005-'08.
3) Prevention and treatment efforts must be expanded to reduce the number of HCV infections among IDUs.
NOTE: The study and the accompanying editorial are available online. They are embargoed until 12:01 a.m. EST on Monday, Jan. 31, 2011:
"Changes in Blood-borne Infection Risk Among Injection Drug Users" http://www.oxfordjournals.org/our_journals/jid/jiq112.pdf
"Prevention of Hepatitis C Virus in Injecting Drug Users: A Narrow Window of Opportunity" http://www.oxfordjournals.org/our_journals/jid/jiq111.pdf
Founded in 1904, The Journal of Infectious Diseases is the premier publication in the Western Hemisphere for original research on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune mechanisms. Articles in JID include research results from microbiology, immunology, epidemiology, and related disciplines. JID is published under the auspices of the Infectious Diseases Society of America (IDSA). Based in Arlington, Va., IDSA is a professional society representing more than 9,000 physicians and scientists who specialize in infectious diseases. For more information, visit http://www.idsociety.org/.
Source
Treatment of hepatitis C virus infection in patients with end-stage renal disease
J Gastroenterol Hepatol. 2011 Feb;26(2):228-39. doi: 10.1111/j.1440-1746.2010.06488.x.
Liu CH, Kao JH.
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Abstract
Hepatitis C virus (HCV) infection is a major health problem in patients with end-stage renal disease (ESRD). The incidence of acute HCV infection during maintenance dialysis is much higher than that in the general population because of the risk of nosocomial transmission. Following acute HCV infection, most patients develop chronic HCV infection, and a significant proportion develop chronic hepatitis, cirrhosis, and even hepatocellular carcinoma. Overall, chronic hepatitis C patients on hemodialysis bear an increased risk of liver-related morbidity and mortality, either during dialysis or after renal transplantation. Interferon (IFN) therapy is modestly effective for the treatment of HCV infection in ESRD patients. Conventional or pegylated IFN monotherapy has been used to treat acute hepatitis C in ESRD patients with excellent safety and efficacy. Regarding chronic hepatitis C, approximately one-third of patients can achieve a sustained virological response (SVR) after conventional or pegylated IFN monotherapy. The combination of low-dose ribavirin and conventional or pegylated IFN has further improved the SVR rate in treatment-naïve or retreated ESRD patients in clinical trials. Similar to the treatment of patients with normal renal function, baseline and on-treatment HCV virokinetics are useful to guide optimized therapy in ESRD patients. Of particular note, IFN-based therapy is not recommended at the post-renal transplantation stage because of the low SVR rate and risk of acute graft rejection. In conclusion, ESRD patients with HCV infection should be encouraged to receive antiviral therapy, and those who achieve an SVR usually have long-term, durable, virological, biochemical, and histological responses.
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
PMID: 21261711 [PubMed - in process]
Source
Liu CH, Kao JH.
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Abstract
Hepatitis C virus (HCV) infection is a major health problem in patients with end-stage renal disease (ESRD). The incidence of acute HCV infection during maintenance dialysis is much higher than that in the general population because of the risk of nosocomial transmission. Following acute HCV infection, most patients develop chronic HCV infection, and a significant proportion develop chronic hepatitis, cirrhosis, and even hepatocellular carcinoma. Overall, chronic hepatitis C patients on hemodialysis bear an increased risk of liver-related morbidity and mortality, either during dialysis or after renal transplantation. Interferon (IFN) therapy is modestly effective for the treatment of HCV infection in ESRD patients. Conventional or pegylated IFN monotherapy has been used to treat acute hepatitis C in ESRD patients with excellent safety and efficacy. Regarding chronic hepatitis C, approximately one-third of patients can achieve a sustained virological response (SVR) after conventional or pegylated IFN monotherapy. The combination of low-dose ribavirin and conventional or pegylated IFN has further improved the SVR rate in treatment-naïve or retreated ESRD patients in clinical trials. Similar to the treatment of patients with normal renal function, baseline and on-treatment HCV virokinetics are useful to guide optimized therapy in ESRD patients. Of particular note, IFN-based therapy is not recommended at the post-renal transplantation stage because of the low SVR rate and risk of acute graft rejection. In conclusion, ESRD patients with HCV infection should be encouraged to receive antiviral therapy, and those who achieve an SVR usually have long-term, durable, virological, biochemical, and histological responses.
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
PMID: 21261711 [PubMed - in process]
Source
Chemoprevention of hepatocellular carcinoma in chronic hepatitis C
Recent Results Cancer Res. 2011;188:85-99.
Morgan TR.
Gastroenterology Section, VA Long Beach Healthcare System, 5901 E. Seventh Street - 11, Long Beach, CA, 90822, USA, timothy.morgan@va.gov.
Abstract
Hepatitis C virus (HCV) infection causes chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma (HCC). The incidence of hepatocellular carcinoma in the United States tripled between 1975 and 2005, and is expected to increase further, and to remain elevated for more than 20 years. Curing hepatitis C infection in patients with cirrhosis through treatment with peginterferon and ribavirin reduces the risk of developing hepatocellular carcinoma. Several noncurative treatments also appear to reduce the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Prospective studies report a reduced incidence of hepatocellular carcinoma among patients treated with a mixture of carotenoids with or without myo-inositol, with vitamin K(2), or with polyprenoic acid (an acyclic retinoid). Uncontrolled and/or retrospective studies have reported beneficial effects of treatment with Sho-saiko-to, glycyrrhizin and ursodeoxycholic acid on hepatocellular carcinoma incidence. Meta-analyses of epidemiologic studies show a reduced risk of hepatocellular carcinoma among liver disease patients who drink two or more cups of coffee per day. Numerous agents prevent or reduce hepatocarcinogenesis in animal models. An ongoing Phase II clinical trial is evaluating S-adenosylmethionine (SAMe) as a potential chemopreventive agent in hepatitis C cirrhosis. Overall, these data suggest that chemoprevention of hepatocellular carcinoma in patients with chronic hepatitis C is an achievable objective.
PMID: 21253791 [PubMed - in process]
Source
Morgan TR.
Gastroenterology Section, VA Long Beach Healthcare System, 5901 E. Seventh Street - 11, Long Beach, CA, 90822, USA, timothy.morgan@va.gov.
Abstract
Hepatitis C virus (HCV) infection causes chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma (HCC). The incidence of hepatocellular carcinoma in the United States tripled between 1975 and 2005, and is expected to increase further, and to remain elevated for more than 20 years. Curing hepatitis C infection in patients with cirrhosis through treatment with peginterferon and ribavirin reduces the risk of developing hepatocellular carcinoma. Several noncurative treatments also appear to reduce the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Prospective studies report a reduced incidence of hepatocellular carcinoma among patients treated with a mixture of carotenoids with or without myo-inositol, with vitamin K(2), or with polyprenoic acid (an acyclic retinoid). Uncontrolled and/or retrospective studies have reported beneficial effects of treatment with Sho-saiko-to, glycyrrhizin and ursodeoxycholic acid on hepatocellular carcinoma incidence. Meta-analyses of epidemiologic studies show a reduced risk of hepatocellular carcinoma among liver disease patients who drink two or more cups of coffee per day. Numerous agents prevent or reduce hepatocarcinogenesis in animal models. An ongoing Phase II clinical trial is evaluating S-adenosylmethionine (SAMe) as a potential chemopreventive agent in hepatitis C cirrhosis. Overall, these data suggest that chemoprevention of hepatocellular carcinoma in patients with chronic hepatitis C is an achievable objective.
PMID: 21253791 [PubMed - in process]
Source
Peregrine Completes Patient Enrollment in Phase Ib HCV/HIV Coinfection Trial
Jan 31, 2011 08:00 ET
Clinical Data From Targeted Antibody Bavituximab Expected in 2Q11
TUSTIN, CA--(Marketwire - January 31, 2011) - Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), a clinical-stage biopharmaceutical company developing first-in-class monoclonal antibodies for the treatment of cancer and viral infections, today announced the completion of enrollment in the company's Phase Ib dose escalation safety study of bavituximab in patients coinfected with chronic hepatitis C virus (HCV) and HIV. Previously this month, Peregrine initiated a randomized Phase II HCV trial to evaluate 12 weeks of therapy with bavituximab, a phosphatidylserine (PS)-targeting monoclonal antibody with immune-modulating potential, in combination with the antiviral drug ribavirin versus standard of care, pegylated interferon alpha 2a and ribavirin.
"Completion of enrollment in our third Phase I HCV trial is an important milestone for our bavituximab antiviral program, and sets the stage for reporting clinical data at a medical conference in the second quarter of this year while we begin to evaluate combination treatment with the antiviral agent ribavirin in a recently initiated study," said Steven W. King, president and chief executive officer of Peregrine. "Though standard treatment for chronic HCV may soon evolve with the introduction of new targeted antiviral drug candidates, immune stimulation with interferon remains a critical component of therapy. Preclinical data support the potential combination of bavituximab and ribavirin and we look forward to seeing how this combination initially compares to standard interferon and ribavirin treatment for 12 weeks in our Phase II study for patients infected with HCV."
In prior HCV clinical trials, bavituximab administered as monotherapy in single and multiple doses demonstrated a positive safety profile with no dose-limiting toxicities or serious adverse events. Bavituximab as a monotherapy also showed promising on therapy antiviral activity of up to 1.5 log viral load reduction.
Bavituximab may address a fundamental "immune evasion" mechanism exploited by many infectious pathogens. A growing body of published data from researchers worldwide shows that bavituximab's PS target, exposed on the surface of cells infected by viruses and protozoan parasites, suppresses the immune system's ability to fight disease. PS-targeting antibodies such as bavituximab bind to PS and block the immunosuppressive signals created by the target, thereby allowing the immune system to mount a robust immune response against the pathogen.
About the Phase Ib HCV Trial
Peregrine's open-label, dose escalation safety study is designed to assess the safety and of bavituximab in up to 24 patients chronically infected with HCV and HIV. Patient cohorts received ascending dose levels of bavituximab weekly for up to 8 weeks. Primary endpoints include safety and pharmacokinetics, and secondary endpoints will measure HCV and HIV RNA by PCR. For further information about Peregrine's HCV trials, please visit http://www.peregrinetrials.com/ or http://www.clinicaltrials.gov/ct2/results?term=bavituximab.
About HCV
According to the U.S. Centers for Disease Control and Prevention, an estimated 3.2 million individuals in the United States have chronic hepatitis C virus (HCV) infection. Chronic HCV infection is a serious disease that can result in long-term health problems, including liver damage, liver failure, liver cancer, or death. It is the leading cause of cirrhosis and liver cancer and the most common reason for liver transplant in the United States. Approximately 8,000 to 10,000 people die every year from HCV-related liver disease.
About Bavituximab's Antiviral Approach
Bavituximab is the first in a new class of patented antibody therapeutics that target and bind to phosphatidylserine (PS), a specific phospholipid component of cell membranes. Bavituximab helps reactivate and direct the body's immune system to destroy infected cells and virus particles that exhibit this specific phospholipid on their surface. Since their target is host-derived rather than pathogen-derived, PS-targeting antibodies have the potential for broad-spectrum antiviral activity and are also expected to be much less susceptible to the viral mutations that often lead to drug resistance.
Researchers have found that PS is exposed on the outer membrane of cells infected with HCV, HIV, influenza, herpes viruses, hemorrhagic fever viruses, respiratory syncytial virus, measles as well as other viruses. A growing body of scientific publications, including Nature Medicine and The Journal of Experimental Medicine, has highlighted data on the role of PS and Peregrine's PS-targeting therapies in infectious diseases.
About Peregrine Pharmaceuticals
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials for the treatment of cancer and serious viral infections. The company is pursuing multiple clinical programs in cancer and hepatitis C virus infection with its lead product candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. (www.avidbio.com), which provides development and biomanufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at http://www.peregrineinc.com/.
Safe Harbor Statement: Statements in this press release which are not purely historical, including statements regarding Peregrine Pharmaceuticals' intentions, hopes, beliefs, expectations, representations, projections, plans or predictions of the future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The forward-looking statements involve risks and uncertainties including, but not limited to, the risk that results from the Phase Ib or Phase II HCV trials will not be consistent with results experienced in earlier HCV clinical trials and preclinical studies, the risk that investigators may experience delays in patient enrollment, risk that results may not support registration filings with the U.S. Food and Drug Administration, and the risk that Peregrine may not have or raise adequate financial resources to complete the planned clinical programs. Factors that could cause actual results to differ materially or otherwise adversely impact the company's ability to obtain regulatory approval for its product candidates include, but are not limited to, uncertainties associated with completing preclinical and clinical trials for our technologies; the early stage of product development; the significant costs to develop our products as all of our products are currently in development, preclinical studies or clinical trials; obtaining additional financing to support our operations and the development of our products; obtaining regulatory approval for our technologies; anticipated timing of regulatory filings and the potential success in gaining regulatory approval and complying with governmental regulations applicable to our business. Our business could be affected by a number of other factors, including the risk factors listed from time to time in the company's SEC reports including, but not limited to, the annual report on Form 10-K for the year ended April 30, 2010 and the quarterly report on Form 10-Q for the quarter ended October 31, 2010. The company cautions investors not to place undue reliance on the forward-looking statements contained in this press release. Peregrine Pharmaceuticals, Inc. disclaims any obligation, and does not undertake to update or revise any forward-looking statements in this press release.
Peregrine Contact:
Amy Figueroa
Peregrine Pharmaceuticals
(800) 987-8256
info@peregrineinc.com
Source
Clinical Data From Targeted Antibody Bavituximab Expected in 2Q11
TUSTIN, CA--(Marketwire - January 31, 2011) - Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), a clinical-stage biopharmaceutical company developing first-in-class monoclonal antibodies for the treatment of cancer and viral infections, today announced the completion of enrollment in the company's Phase Ib dose escalation safety study of bavituximab in patients coinfected with chronic hepatitis C virus (HCV) and HIV. Previously this month, Peregrine initiated a randomized Phase II HCV trial to evaluate 12 weeks of therapy with bavituximab, a phosphatidylserine (PS)-targeting monoclonal antibody with immune-modulating potential, in combination with the antiviral drug ribavirin versus standard of care, pegylated interferon alpha 2a and ribavirin.
"Completion of enrollment in our third Phase I HCV trial is an important milestone for our bavituximab antiviral program, and sets the stage for reporting clinical data at a medical conference in the second quarter of this year while we begin to evaluate combination treatment with the antiviral agent ribavirin in a recently initiated study," said Steven W. King, president and chief executive officer of Peregrine. "Though standard treatment for chronic HCV may soon evolve with the introduction of new targeted antiviral drug candidates, immune stimulation with interferon remains a critical component of therapy. Preclinical data support the potential combination of bavituximab and ribavirin and we look forward to seeing how this combination initially compares to standard interferon and ribavirin treatment for 12 weeks in our Phase II study for patients infected with HCV."
In prior HCV clinical trials, bavituximab administered as monotherapy in single and multiple doses demonstrated a positive safety profile with no dose-limiting toxicities or serious adverse events. Bavituximab as a monotherapy also showed promising on therapy antiviral activity of up to 1.5 log viral load reduction.
Bavituximab may address a fundamental "immune evasion" mechanism exploited by many infectious pathogens. A growing body of published data from researchers worldwide shows that bavituximab's PS target, exposed on the surface of cells infected by viruses and protozoan parasites, suppresses the immune system's ability to fight disease. PS-targeting antibodies such as bavituximab bind to PS and block the immunosuppressive signals created by the target, thereby allowing the immune system to mount a robust immune response against the pathogen.
About the Phase Ib HCV Trial
Peregrine's open-label, dose escalation safety study is designed to assess the safety and of bavituximab in up to 24 patients chronically infected with HCV and HIV. Patient cohorts received ascending dose levels of bavituximab weekly for up to 8 weeks. Primary endpoints include safety and pharmacokinetics, and secondary endpoints will measure HCV and HIV RNA by PCR. For further information about Peregrine's HCV trials, please visit http://www.peregrinetrials.com/ or http://www.clinicaltrials.gov/ct2/results?term=bavituximab.
About HCV
According to the U.S. Centers for Disease Control and Prevention, an estimated 3.2 million individuals in the United States have chronic hepatitis C virus (HCV) infection. Chronic HCV infection is a serious disease that can result in long-term health problems, including liver damage, liver failure, liver cancer, or death. It is the leading cause of cirrhosis and liver cancer and the most common reason for liver transplant in the United States. Approximately 8,000 to 10,000 people die every year from HCV-related liver disease.
About Bavituximab's Antiviral Approach
Bavituximab is the first in a new class of patented antibody therapeutics that target and bind to phosphatidylserine (PS), a specific phospholipid component of cell membranes. Bavituximab helps reactivate and direct the body's immune system to destroy infected cells and virus particles that exhibit this specific phospholipid on their surface. Since their target is host-derived rather than pathogen-derived, PS-targeting antibodies have the potential for broad-spectrum antiviral activity and are also expected to be much less susceptible to the viral mutations that often lead to drug resistance.
Researchers have found that PS is exposed on the outer membrane of cells infected with HCV, HIV, influenza, herpes viruses, hemorrhagic fever viruses, respiratory syncytial virus, measles as well as other viruses. A growing body of scientific publications, including Nature Medicine and The Journal of Experimental Medicine, has highlighted data on the role of PS and Peregrine's PS-targeting therapies in infectious diseases.
About Peregrine Pharmaceuticals
Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials for the treatment of cancer and serious viral infections. The company is pursuing multiple clinical programs in cancer and hepatitis C virus infection with its lead product candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. (www.avidbio.com), which provides development and biomanufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at http://www.peregrineinc.com/.
Safe Harbor Statement: Statements in this press release which are not purely historical, including statements regarding Peregrine Pharmaceuticals' intentions, hopes, beliefs, expectations, representations, projections, plans or predictions of the future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The forward-looking statements involve risks and uncertainties including, but not limited to, the risk that results from the Phase Ib or Phase II HCV trials will not be consistent with results experienced in earlier HCV clinical trials and preclinical studies, the risk that investigators may experience delays in patient enrollment, risk that results may not support registration filings with the U.S. Food and Drug Administration, and the risk that Peregrine may not have or raise adequate financial resources to complete the planned clinical programs. Factors that could cause actual results to differ materially or otherwise adversely impact the company's ability to obtain regulatory approval for its product candidates include, but are not limited to, uncertainties associated with completing preclinical and clinical trials for our technologies; the early stage of product development; the significant costs to develop our products as all of our products are currently in development, preclinical studies or clinical trials; obtaining additional financing to support our operations and the development of our products; obtaining regulatory approval for our technologies; anticipated timing of regulatory filings and the potential success in gaining regulatory approval and complying with governmental regulations applicable to our business. Our business could be affected by a number of other factors, including the risk factors listed from time to time in the company's SEC reports including, but not limited to, the annual report on Form 10-K for the year ended April 30, 2010 and the quarterly report on Form 10-Q for the quarter ended October 31, 2010. The company cautions investors not to place undue reliance on the forward-looking statements contained in this press release. Peregrine Pharmaceuticals, Inc. disclaims any obligation, and does not undertake to update or revise any forward-looking statements in this press release.
Peregrine Contact:
Amy Figueroa
Peregrine Pharmaceuticals
(800) 987-8256
info@peregrineinc.com
Source
Hepatitis C virus Resistance to Protease Inhibitors
Philippe Halfon a, Stephen Locarnini b
Received 13 December 2010; received in revised form 20 January 2011; accepted 20 January 2011. published online 31 January 2011.
Accepted Manuscript
Abstract
Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA) against HCV, include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase and NS5A inhibitors at various stages of clinical development. The rapid replication rate of HCV, along with the low fidelity of its polymerase, gives rise to the generation of mutations throughout the viral genome resulting in remarkable sequence variation in the HCV population, known as a quasispecies. The efficacy of DAAs is limited by the presence of these mutations resulting in amino-acid substitutions within the targeted proteins which affect viral sensitivity to these compounds. Thus, due to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Not surprisingly then, these changes are selected in patients either breaking through or not responding to potent DAA treatment. Six major position mutations in the NS3 HCV Protease (36, 54, 155, 156, 168, and 170) have now been reported in vitro or in vivo associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/ subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA sensitivity. Different amino acid diversity profiles for HCV genotypes/subtypes suggest differences in the position/ type of immune escape and drug resistance mutations. Also, different pathways of resistance profiles based on the chemical scaffold (linear or macrocyclic) of the protease inhibitors have been described. This review first describes how resistance to a protease inhibitor can develop and then provides an overview of the mechanism of how particular mutations confer varying levels of resistance to protease inhibitor, which have been identified and characterized using both genotypic and phenotypic tools. Future potential therapeutic strategies to assist patients who do develop resistance to protease inhibitors are also outlined. The challenge developing new HCV protease inhibitors should take in consideration not only the antiviral potency of the drugs, the occurrence and importance of side effects, the frequency of oral administration, but also the resistance profiles of these agents
a Virological Departement Laboratoire Alphabio, Hôpital Ambroise Paré, Marseille, France
b Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
PII: S0168-8278(11)00079-1
doi:10.1016/j.jhep.2011.01.011
© 2011 Published by Elsevier Inc.
Source
Received 13 December 2010; received in revised form 20 January 2011; accepted 20 January 2011. published online 31 January 2011.
Accepted Manuscript
Abstract
Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA) against HCV, include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase and NS5A inhibitors at various stages of clinical development. The rapid replication rate of HCV, along with the low fidelity of its polymerase, gives rise to the generation of mutations throughout the viral genome resulting in remarkable sequence variation in the HCV population, known as a quasispecies. The efficacy of DAAs is limited by the presence of these mutations resulting in amino-acid substitutions within the targeted proteins which affect viral sensitivity to these compounds. Thus, due to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Not surprisingly then, these changes are selected in patients either breaking through or not responding to potent DAA treatment. Six major position mutations in the NS3 HCV Protease (36, 54, 155, 156, 168, and 170) have now been reported in vitro or in vivo associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/ subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA sensitivity. Different amino acid diversity profiles for HCV genotypes/subtypes suggest differences in the position/ type of immune escape and drug resistance mutations. Also, different pathways of resistance profiles based on the chemical scaffold (linear or macrocyclic) of the protease inhibitors have been described. This review first describes how resistance to a protease inhibitor can develop and then provides an overview of the mechanism of how particular mutations confer varying levels of resistance to protease inhibitor, which have been identified and characterized using both genotypic and phenotypic tools. Future potential therapeutic strategies to assist patients who do develop resistance to protease inhibitors are also outlined. The challenge developing new HCV protease inhibitors should take in consideration not only the antiviral potency of the drugs, the occurrence and importance of side effects, the frequency of oral administration, but also the resistance profiles of these agents
a Virological Departement Laboratoire Alphabio, Hôpital Ambroise Paré, Marseille, France
b Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
PII: S0168-8278(11)00079-1
doi:10.1016/j.jhep.2011.01.011
© 2011 Published by Elsevier Inc.
Source
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