Monday, April 9, 2012
Promising Vaccine Targets On Hepatitis C Virus
HCV's very high rate of mutation normally helps it to evade its host's immune system. The newly discovered antibodies, however, attach to sites on the viral envelope that seldom mutate. One of the new antibodies, AR4A, shows broader HCV neutralizing activity than any previously reported anti-HCV antibody.
"These antibodies attach to sites on the viral envelope that were previously unknown, but now represent promising targets for an HCV vaccine," said Mansun Law, an assistant professor at Scripps Research. Law is the senior author of the new report, which appears online this week in the Proceedings of the National Academy of Sciences.
A Desperate Need
An effective HCV vaccine is desperately needed. The World Health Organization (WHO) estimates that the virus has established mostly silent infections in 130 to 170 million people worldwide -- nearly 3 percent of the human population -- and spreads to 3 to 4 million new people annually. HCV principally infects liver cells, and is thought to cause chronic, often-unnoticed liver inflammation, which eventually can lead to serious liver ailments. The virus already is responsible for about a quarter of annual US cases of liver cirrhosis and primary liver cancer, and it is the leading cause of liver transplants. In some developing countries, HCV prevalence is extremely high; studies suggest that in Egypt, as many as 22 percent of the population is infected -- apparently due to poor screening of blood products and past re-use of syringes. Even in developed countries, HCV infections represent a looming public health crisis. In the United States and Europe, up to 14 million people are now HCV-positive, and each year an estimated 150,000 people are newly infected.
The current leading treatment for HCV infection involves a 12- to 36-week course of the immune-stimulating protein interferon-alpha, the antiviral drug ribavirin and HCV protease blocker. But it is not completely effective, and it causes significant adverse side effects -- aside from being very expensive. To fully stamp out the HCV pandemic, especially in developing countries, scientists will have to develop a cheap preventive vaccine.
Yet an effective HCV vaccine has so far been elusive. The virus mutates very rapidly, and thus, antibodies raised against one isolate of HCV typically won't protect against a subsequent HCV infection. Hospital samples of HCV suggest that the virus's genes, and the proteins for which they code, are highly variable even within an individual patient.
"One of the big goals of HCV vaccine development has been to find an accessible spot on the virus that doesn't change constantly," said Law.
Searching for Vulnerabilities
To find such vulnerable spots, researchers sift through antibodies sampled from infected people and look for those antibodies that can neutralize a broad range of viral strains. The locations on the virus where those broadly neutralizing antibodies bind mark the vulnerable viral structures that can be used as the bases of a broadly effective, antibody-stimulating vaccine. Previous studies, including a 2008 study in Nature Medicine, for which Law was lead author, have found some broadly neutralizing HCV antibodies. But for the present study, Law and his colleagues used a more thorough approach, known as "exhaustive panning," to see if they could find new and even more broadly neutralizing antibodies. "Exhaustive panning is a powerful technique for finding rare antibodies that might otherwise go undetected," Law said.
HCV employs a complex of two envelope glycoproteins, E1 and E2, to grab and fuse with target cells. Erick Giang, a research assistant in Law's lab, harvested this viral E1-E2 complex from HCV-producing cells in a lab dish and used it as "bait" for a panel of antibodies derived from the blood of a person with chronic HCV infection. The exhaustive panning technique involves exposing this bait protein to different anti-HCV antibodies in sequence, so that the known antibody-binding sites on the complex are progressively covered until only new ones are left.
In this way, Giang catalogued 73 new anti-HCV antibodies, which bind to five distinct "antigenic regions" on the E1-E2 complex. In standard cell culture tests of HCV-neutralizing ability, several of these antibodies showed an ability to neutralize infection by a wide range of HCV strains. One, AR4A, turned out to bind to an almost-unvarying spot on E1-E2 complex, close to the surface of the virus's outer coat of fat molecules. AR4A showed significant neutralizing ability against all 22 HCV strains in a test panel -- not only in tests in Law's lab, but also in confirmatory tests at the University of Copenhagen.
The Broadest Neutralizing Activity Yet
The new antibody thus is more broadly protective than the previous top contender, AR3A, which Law described in his 2008 Nature Medicine paper. "This human antibody AR4A has the broadest HCV-neutralizing activity known to the field," Law said.
Collaborating researchers at Rockefeller University, who recently engineered a line of HCV-infectable mice, showed that AR4A antibodies protected these mice from two widely different HCV strains. A combination of half-doses of AR3A and AR4A antibodies worked less well.
The next step for Law and his colleagues is to start making and testing prototype vaccines based on the vulnerable HCV binding sites that have been revealed by these antibody studies. The researchers also plan to use the new antibodies to study the structure and function of HCV proteins such as the all-important E1-E2 complex.
Anti-HCV antibodies such as AR4A and AR3A could have some therapeutic use, too. Although they wouldn't be able to clear existing HCV infections and would be too expensive and difficult to use on a large population to prevent new infections, they could be useful in preventing new HCV liver infections in liver transplant patients. Such infections can spread from HCV reservoirs in the patient's body to the newly transplanted liver tissue.
"Antibody-based treatment has worked extremely well for liver transplants to patients with hepatitis B virus, and we hope the new HCV antibodies can be just as helpful to HCV liver transplant patients," Law said.
In addition to Law and Giang, contributors to the paper, "Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus," were Marcus Dorner, Charles M. Rice, and Alexander Ploss of Rockefeller University in New York; Jannick C. Prentoe and Jens Bukh of the University of Copenhagen; Matthew J. Evans of the Mount Sinai School of Medicine; and Marlène Dreux and Dennis Burton at Scripps Research.
The Law laboratory's research is supported by the National Institutes of Health.
Bristol-Gilead Hep C Drug Data Leaks
Updated with a corrected research report from Jefferies, noting that the end-of-treatment response to daclatasvir and GS-7977 was actually 97%, not 93%. -- An early peek at data from a closely watched mid-stage study combining hepatitis C drugs from Bristol-Myers Squibb(BMY_) andGilead Sciences(GILD_) has leaked in advance of the European Association for the Study of the Liver (EASL) annual meeting.
--Written by Adam Feuerstein in Boston.ad Hep C Drug Data Leaks
common side effects for peginterferon
The most common side effects for peginterferon (such as Pegasys or PegIntron) are fatigue, headache, fever, muscle pain and chills. However, other possible side effects are listed below. Although these side effects are specifically for Pegasys (a brand name peginterferon alfa-2a drug for treating hepatitis C and sometimeshepatitis B), they are similar to any other peginterferon such as PegIntron.
of the study group reported this side effect.
How Are These Side effects Determined?
Before a drug (such as Pegasys) can be licensed as an approved treatment for hepatitis B and hepatitis C, it has to be tested in clinical trials. Clinical trials are scientific studies that determine if the drug is safe and what are the side effects. The side effects listed below were determined by treating 559 people with 180 micrograms of Pegasys for 48 weeks. The number listed after each side effect is the percentage of the 559 people in the clinical trial who reported that particular side effect.How to Understand This List of Side Effects
This list of side effects is arranged in order of frequency, which means that more people in the study group reported the side effects at the beginning of the list than at the end of the list. Since peginterferon will react a little differently in each person, this list should be considered only as a general guide. However, by using the list below, doctors know that about half of their patients on peginterferon will suffer fatigue and can then help prepare them for this.Should I Be Concerned about These Side Effects?
You should absolutely know and understand these side effects. Sometimes it's helpful to know what the side effects are so that you can better prepare for them. For example, if you have trouble with depression, taking this medication could worsen your usual episodes because almost 20% of people report depression while on this medicine. By knowing that depression is a potential side effect, you and your doctor can discuss solutions such as prescribing antidepressants before you begin this treatment.
It's also important not to be discouraged by these side effects. Every medication will have some unwanted effects, but taking this drug gives you the best chance of a successful treatment in exchange for having side effects. As potentially better treatments are introduced, you can compare their effectiveness against their side effects and, with your doctor, make an informed decision on your treatment.
Where Do I Get This Information?
The side effects (also called adverse reactions) of every drug must be determined through extensive clinical trials before the drug can legally be sold in the United States. The source of this list is from the Pegasys package insert which can be read from the drug manufacturer or the US Food and Drug Administration.| A Complete List of Peginterferon Side Effects | |
| Side Effect | Percentage Reporting |
| Fatigue | 56% |
| Headache | 54% |
| Fever (pyrexia) | 37% |
| Muscle pain (myalgia) | 37% |
| Shivering (Rigors) | 35% |
| Joint pain (arthralgia) | 28% |
| Nausea/Vomiting | 24% |
| Hair loss (alopecia) | 23% |
| Injection site reaction | 22% |
| Neutropenia | 21% |
| Irritability and nervousness | 19% |
| Trouble sleeping (insomnia) | 19% |
| Depression | 18% |
| Loss of appetite (anorexia) | 17% |
| Diarrhea | 16% |
| Dizziness (not vertigo) | 16% |
| Belly pain | 15% |
| Itchiness (pruritus) | 12% |
| Pain | 11% |
| Resistance Mechanism Disorders | 10% |
| Back pain | 9% |
| Dermatitis | 8% |
| Trouble concentrating | 8% |
| Dry mouth | 6% |
| Increased sweating | 6% |
| Loss of some memory | 5% |
| Rash | 5% |
| Thrombocytopenia | 5% |
| Blurry vision | 4% |
| Cough | 4% |
| Dry skin | 4% |
| Shortness of breath (dyspnea) | 4% |
| Weight loss | 4% |
| Changes in mood | 3% |
| Hypothyroidism | 3% |
| Lymphopenia | 3% |
| Anemia | 2% |
| Eczema (general skin inflammation) | 1% |
| Shortness of breath on exertion | <1%* |
| Upset stomach (dyspepsia) | <1%* |
| *This means that less than 1% | |
Source 
Hepatitis
What Is Riba Rage?
What Is Riba Rage?
From Charles Daniel, former About.com Guide
About.com Health's Disease and Condition content is reviewed by the Medical Review Board
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Question: What Is Riba Rage?
Answer: Riba rage is the popular, though misleading, name for certain side effects from treating chronic hepatitis. Chronic hepatitis C is usually treated with a combination of two drugs: pegylated interferon (either Peginterferon Alfa-2a or Peginterferon Alfa-2b) and ribavirin. This combination therapy is considered to have good treatment results, with sustained response rates up to 55% in many patients with Hepatitis C Virus (HCV) genotype 1. This means that more than half of the patients using this treatment will have undetectable levels of HCV in their blood 6 months after finishing treatment. For people with HCV genotypes 2 or 3, the sustained response rate is up to 80%.
- PEGINTERFERON ALFA-2a is a man-made drug that acts like a protein made by the body. It is used to treat chronic hepatitis B and C infections.
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.
Your health care provider needs to know if you have any of these conditions:
•alcoholism
•auto-immune hepatitis
•blood or bleeding disorders
•colitis like ulcerative colitis or Crohn's disease
•depression or other mental disorders
•diabetes
•drug abuse or addiction
•heart disease
•history of cancer
•kidney disease
•lupus
•psoriasis
•rheumatoid arthritis
•thyroid problems
•an unusual or allergic reaction to peginterferon, other medicines, foods, dyes, or preservatives like benzyl alcohol
•pregnant or trying to get pregnantSide effects that you should report to your doctor or health care professional as soon as possible:•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•bloody diarrhea
•breathing problems
•change in blood sugar
•changes in vision
•chest pain
•fast, irregular heartbeat
•fever
•high blood pressure
•increased anger, depression, irritability, or thoughts of suicide
•pain in lower back or stomach
•pain, tingling, numbness in the hands or feet
•trouble passing urine or change in the amount of urine
•unusual bleeding or bruising
Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•aches, pains
•dry, itchy skin
•hair loss
•loss of appetite
•nausea, stomach upset
•pain or swelling at site where injected
•trouble sleeping
•unusually weak or tired
This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Visit your doctor or health care professional for regular checks on your progress. You will need regular blood checks.
You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how this medicine affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol may interfere with the effect of this medicine. Avoid alcoholic drinks. •
While patients generally get good results from this treatment combination, interferon has some nasty side effects. Two of these are depression and general irritability. The type of intense depression and irritability that "heppers" (people with hepatitis) experience while on treatment occurs often enough that it's commonly known as "riba rage," even though it isn't really caused by the ribavirin.
- Treatment Overview
- Living Through Hepatitis C Treatment
- Basics of Hepatitis C
Patients and family members should be aware of any behavior changes during treatment, because most cases of riba rage, if not all, can be controlled with appropriate medical intervention. For those patients who know they already have problems with depression or mood problems, they should be considered for antidepressant therapy at the start of treatment. For those who have had previous problems with depression but are not currently experiencing problems, they should be monitored closely by a mental health team who can quickly begin appropriate treatment. Be sure to seek out a supportive and experienced treatment team that can anticipate and manage these side effects quickly and efficiently.
Source:
Friedman L. Liver, Biliary Tract, & Pancreas. In: McPhee S, Papadakis, M, Tierney, L (eds),Current Medical Diagnosis and Treatment 2007, 46e. McGraw-Hill, 2007. 66
What Are the Side Effects of Ribavirin Treatment?
Question: What Are the Side Effects of Ribavirin Treatment?
Answer: Ribavirin (also known as Copegus or Rebetol) is an antiviral drug that treats hepatitis C and is always prescribed with an interferon (usually peginterferon). Side effects from the combination of ribavirin and interferon (or peginterferon) are common and some people can have them so severe that they interfere with treatment. Since ribavirin can't be used alone as a hepatitis C treatment, the side effects are actually from the combination of ribavirin and an interferon. Here is a list of the most common side effects:
- Anemia, a blood disorder where there aren't enough red blood cells to carry oxygen. The result is that you're tired. After about two weeks of ribavirin treatment, about 10% of people develop a severe form of anemia.
- Headache
- Irritability and anxiety
- Depression. Sometimes people taking ribavirin develop severe depression and can even have suicidal thoughts. These side effects, along with general irritability, are unofficially known as Riba Rage, even though they're really caused by the interferon. For most people, these side effects can be controlled with antidepressants or other medicines. It's important to look for signs of behavioral change during treatment so your doctor can help control any developing depression as quickly as possible. For people with known psychiatric problems, it's possible your doctor will want to start you on a preventative therapy before you start treatment. Some people with severe depression or a history of suicidality may not be able to start treatment of hepatitis C.
- Alopecia (hair loss)
- Itchiness
- Insomnia (having trouble sleeping)
- Arthralgia (joint pain)
- Myalgia (muscle pain)
- Anorexia (loss of appetite)
- Neutropenia. Neutropenia is a blood disorder caused by a loss of neutrophils, a type of white blood cell that destroys bacteria. Neutropenia is probably the result of decreased bone marrow function, which the combination therapy suppresses, and may mean your body will have trouble fighting off bacterial infections.
- Nausea and vomiting
- Fever
- Chills
•thyroid problems
•an unusual or allergic reaction to peginterferon, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding
RIBAVIRIN is an antiviral medicine
RIBAVIRIN is an antiviral medicine. It is used to treat severe respiratory syncytial virus (RSV) in hospitalized children.
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.
Your health care provider needs to know if you have any of these conditions:
•heart problems
•on a ventilator for breathing assistance
•an unusual or allergic reaction to ribavirin, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding
Side effects that you should report to your doctor or health care professional as soon as possible:
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•breathing problems
•chest pain, soreness
•fever
•lips or nail beds with bluish color
•seizures
•unusual blood pressure or heart rate
•unusually weak or tired
Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•headache
•irritated, watery eyes
•runny nose
This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Your condition will be monitored carefully while you are receiving this medicine.
Visitors and health care workers are at risk of exposure to this medicine by breathing mist from the air. Talk to the doctor for more information. If you are pregnant or breast-feeding talk with the doctor before visiting a patient who is on this medicine.
Do not become pregnant while taking this medicine. Women should inform their doctor if they wish to become pregnant or think they might be pregnant. There is a potential for serious side effects to an unborn child. Talk to your health care professional or pharmacist for more information. The following drugs may interact with Ribavirin:•medicines to treat HIV like zidovudine (AZT), lamivudine, stavudine (d4T)
This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.
How should I use this medicine?This medicine is for inhalation through the mouth. It is given by specially trained personnel in a hospital setting.
Talk to your pediatrician regarding the use of this medicine in children. While this drug may be prescribed for selected conditions, precautions do apply.
Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.
Your health care provider needs to know if you have any of these conditions:
•heart problems
•on a ventilator for breathing assistance
•an unusual or allergic reaction to ribavirin, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding
Side effects that you should report to your doctor or health care professional as soon as possible:
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•breathing problems
•chest pain, soreness
•fever
•lips or nail beds with bluish color
•seizures
•unusual blood pressure or heart rate
•unusually weak or tired
Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•headache
•irritated, watery eyes
•runny nose
This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Your condition will be monitored carefully while you are receiving this medicine.
Visitors and health care workers are at risk of exposure to this medicine by breathing mist from the air. Talk to the doctor for more information. If you are pregnant or breast-feeding talk with the doctor before visiting a patient who is on this medicine.
Do not become pregnant while taking this medicine. Women should inform their doctor if they wish to become pregnant or think they might be pregnant. There is a potential for serious side effects to an unborn child. Talk to your health care professional or pharmacist for more information. The following drugs may interact with Ribavirin:•medicines to treat HIV like zidovudine (AZT), lamivudine, stavudine (d4T)
This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.
How should I use this medicine?This medicine is for inhalation through the mouth. It is given by specially trained personnel in a hospital setting.
Talk to your pediatrician regarding the use of this medicine in children. While this drug may be prescribed for selected conditions, precautions do apply.
Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.
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