Genetic engineering, increased understanding of the immune system and new immunization delivery technologies could make this century the golden age of vaccines, observers say.
By Christine S. Moyer, amednews staff. Posted July 19, 2010.
One night in 1961, William Schaffner, MD, was called to a New York City hospital to assist with an emergency lumbar puncture on a child critically ill with Haemophilus influenzae type b meningitis.
At the time -- before a vaccine was developed -- Hib disease was the leading cause of bacterial meningitis among children younger than 5. It infected about 20,000 U.S. children and killed nearly 1,000 annually.
In the nearly 50 years since Dr. Schaffner, an infectious disease specialist, saw that child with Hib disease, he has seen vaccine developments that have changed medicine and saved scores of lives.
"My comment used to be that pediatric residents read about [Hib] disease, but they don't see it anymore. Now they don't even read about it," said Dr. Schaffner, professor of medicine and preventive medicine and chair of the Dept. of Preventive Medicine at Vanderbilt University School of Medicine in Nashville, Tenn.
During the past two decades, the number of diseases that can be prevented by vaccines has doubled, according to the Centers for Disease Control and Prevention.
Since 1990, the Food and Drug Administration has licensed immunizations for Haemophilus influenzae type b, varicella, human papillomavirus, rotavirus and shingles, among others.
Experts say the 21st century holds even more promise for new vaccines.
Application of genetic engineering, an increased understanding of the immune system and new immunization delivery technologies have created what some call the golden age of vaccines.
Scientists are exploring new frontiers where vaccines can be developed in plants. Other possible advancements include using a patch to immunize patients, and treating drug addiction with a vaccine. But such advancements take years or, in some cases, decades to develop and be licensed.
The upswing in vaccine development, after a slowdown in the 1970s and 1980s, has not been without stumbling blocks. The advanced technology used to develop new vaccines has made them too expensive for some physicians to purchase, store and administer. Outdated manufacturing systems have struggled to keep up with demand.
And even the success of vaccines can have negative effects -- some parents choose not to immunize their children, in part, because they no longer think there is a need.
The anti-immunization movement has led to the resurgence of potentially fatal diseases such as mumps and pertussis. California, for example, is on pace to have its highest number of pertussis-related illnesses and deaths in 50 years, according to the state's public health department.
Vaccine developments
Dr. Schaffner views the HPV vaccine as one of the most exciting recent advancements because it demonstrates the potential for vaccine development in the 21st century. One reason is because of the role genetic engineering played in the vaccine's creation.
Research for the HPV vaccine, which was first licensed in 2006, began in the early 1990s, according to Douglas Lowy, MD, an HPV researcher for the National Cancer Institute. He said the NCI lab was the first to show that if a single HPV gene is expressed, it could self-assemble to create virus-like particles. GlaxoSmithKline's Cervarix vaccine and Merck's Gardasil are based on this development, he said.
Cervical cancer was considered a vaccine priority, in part, because of the high number of women diagnosed with the disease, Dr. Lowy added. The American Cancer Society estimated that 11,270 new cases of invasive cervical cancer were diagnosed in 2009. About a third of those women will likely die from the disease.
Underserved populations, particularly Hispanic and black females, are disproportionately affected because they often cannot afford cervical cancer screening.
"The HPV vaccine could be one way, in the long run, to try to address this disparity," Dr. Lowy said.
There are, however, some ethical concerns with the immunization, said Ruth Faden, PhD, MPH, director of Johns Hopkins Berman Institute of Bioethics in Baltimore. Faden said the HPV vaccine is too expensive for many poor nations to purchase. That means the people who need the vaccine the most often do not get it.
A more immediate public health benefit has been experienced with the two rotavirus vaccines, Merck's RotaTeq, licensed in 2006, and GlaxoSmithKline's Rotarix, licensed in 2008. Before the development of the vaccines, rotavirus led to the hospitalization of 55,000 to 70,000 U.S. children each year and caused an estimated 20 to 60 deaths, according to the CDC.
During the 2008-09 rotavirus season, the number of positive rotavirus test results decreased 60% from the pre-vaccine period of 2000-06, the CDC reported in October 2009.
Vaccines of the future
AIDS is one area of focus for tomorrow's vaccines. Experts agree that greater research into the human immune system, and how it works, has contributed to recent advancements in the quest for an AIDS vaccine. HIV/AIDS infects about 50,000 new Americans each year, said James Kublin, MD, MPH, director of the HIV Vaccine Trials Network, an international collaboration of scientists and educators searching for an HIV vaccine.
Globally, about 33.4 million people were HIV positive in 2008, and an estimated 2 million died of AIDS, according to the World Health Organization's most recent data.
"It will be very difficult to treat our way out of this epidemic," Dr. Kublin said.
In 2009, a six-year HIV immunization study in Thailand showed the first evidence of efficacy from an HIV vaccine. Researchers found that participants who received the combination of a priming vaccine and boosting vaccine were 31.2% less likely to get HIV than those who received a placebo, according to a study in the Dec. 3, 2009, New England Journal of Medicine.
Dr. Kublin said an HIV vaccine could be licensed within the next decade.
In July, scientists led by a team from the National Institute of Allergy and Infectious Diseases Vaccine Research Center revealed their discovery of two naturally occurring antibodies that can stop more than 90% of known global HIV strains from infecting human cells in the laboratory. Researchers said the technique used to find these antibodies could be applied to vaccine design for many other infectious diseases.
Some infectious disease experts are heralding the discovery as a significant step toward developing an HIV vaccine. But scientists still have years of research and clinical trials before a safe and effective vaccine is developed.
Research into the immune system factored into advancements made in the development of a cocaine vaccine that is being readied for national multisite study. Principal researcher Thomas R. Kosten, MD, chair and professor of psychiatry, neuroscience and pharmacology at Baylor College of Medicine in Houston, has been working on a cocaine vaccine for about 15 years. The vaccine provokes the body to make antibodies that bind to cocaine and prevent it from leaving the bloodstream. The result is an inability to experience the drug's euphoric effects.
The ethical question, according to Faden, of Johns Hopkins, is whether people who get the cocaine vaccine would start abusing another drug. She said such questions need to be addressed as vaccines for drug abuse are developed.
Other research is looking at more ways to deliver vaccines beyond the needle.
Work is under way to administer the influenza vaccination, along with other immunizations, using a patch lined with tiny micro needles that would be essentially painless, according to Dr. Schaffner. Using a patch also would reduce costs by eliminating the need to refrigerate vaccines, and it would eradicate the safety issues that accompany health professionals handling needles and syringes, he said.
Researchers are also, in various forms, combining work on genetic engineering, immune-system research and new immunization-delivery technologies. For example, Dr. Schaffner said researchers are using recombinant genetics to find ways to include vaccine antigens in edible plants, such as tomatoes and bananas. The idea is that when people eat the food, Dr. Schaffner said, they would receive a vaccine boost.
"That would be an incredible way to administer vaccines to large populations, particularly in the developing world," Dr. Schaffner said. However, the possible introduction of such foods is a long way off, experts said.
Researchers also are developing a universal influenza vaccine, which would provide patients immunity against the flu for multiple years, said Frederick Cassels, PhD, SARS and Influenza Vaccine Program officer for the NIAID. He predicted it likely would take at least 10 years for it to be licensed.
Closer to becoming a reality: adding adjuvant to flu immunizations, which could stretch the vaccine supply and elicit a broader immune response from those who receive it, Cassels said. Also on the horizon are therapeutic vaccines that could extend the lives of cancer patients.
Infectious disease specialist Dr. Schaffner is among those closely watching studies being conducted on potential vaccines. Like others, he is confident that today's diseases will fall victim to tomorrow's vaccine, following the path of Hib and polio -- out of doctors' offices and into the history pages of medical textbooks.
Vaccine timeline
In the past two decades, the number of diseases that can be prevented by vaccines has more than doubled. Here is a time line of vaccine development from 1914 to 2010.
1914: Whole-cell pertussis vaccine licensed.
1923: Diphtheria vaccine licensed.
1924: Tetanus toxoid produced.
1945: Influenza vaccine first used.
1948: Tetanus, diphtheria and pertussis vaccines combined to make DTP vaccine for routine childhood immunization.
1955: Inactivated polio vaccine licensed.
1961: Monovalent oral polio vaccine licensed.
1963: Trivalent oral polio vaccine and measles vaccine licensed.
1967: Mumps vaccine licensed.
1969: Rubella vaccine licensed.
1971: Measles, mumps and rubella vaccine licensed.
1982: Hepatitis B vaccine licensed.
1985: Haemophilus influenzae type b polysaccharide vaccine licensed.
1990: Haemophilus influenzae type b polysaccharide conjugate vaccine licensed for infants.
1991: Acellular pertussis vaccine licensed for use in children 15 months to 6 years old.
1995: Varicella and hepatitis A vaccines licensed.
1996: Acellular pertussis vaccine licensed for use in infants.
1998: First rotavirus vaccine licensed. It was withdrawn a year later due to adverse events.
2000: Pneumococcal conjugate vaccine licensed.
2003: Live attenuated influenza vaccine licensed for people age 5 to 49.
2005: Tetanus, diphtheria, pertussis vaccine licensed for adolescents and adults. A new meningococcal vaccine also licensed for people age 11 to 55.
2006: Vaccines against rotavirus, the human papillomavirus and shingles licensed. A new immunization that combined measles, mumps, rubella and varicella also licensed.
2008: A second rotavirus vaccine licensed.
2009: A second human papillomavirus vaccine and four vaccines against the 2009 A(H1N1) influenza virus licensed. A new high-dose inactivated influenza vaccine for people age 65 and older also licensed.
2010: A second conjugate pneumococcal vaccine licensed.
Source: Centers for Disease Control and Prevention
Weblink
"Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand," New England Journal of Medicine, Dec. 3, 2009 (www.ncbi.nlm.nih.gov/pubmed/19843557)
Centers for Disease Control and Prevention on vaccines and immunizations (www.cdc.gov/vaccines)
HIV Vaccine Trials Network (http://www.hvtn.org/)
National Institute of Allergy and Infectious Diseases on 2009 H1N1, seasonal, avian and pandemic influenzas (www.niaid.nih.gov/topics/flu)
National Cancer Institute fact sheet on cancer vaccines (www.cancer.gov/cancertopics/factsheet/therapy/cancer-vaccines)
Source
July 19, 2010
Foreign clinical trials need stricter controls, HHS study says
Requiring standardized electronic clinical trial data is among a new report's recommendations.
By Tanya Albert Henry, amednews correspondent. Posted July 19, 2010.
More than half of clinical trial subjects and sites for drugs and biologics were located outside the United States in fiscal 2008, a new study said. And 80% of the drug and biologic marketing applications that the Food and Drug Administration approved contained foreign clinical trial data.
Western Europe accounted for 58% of subjects enrolled at foreign sites and 60% of the foreign sites. Central and South America had a significant number, including the highest average number of subjects per site compared to other foreign regions, according to a June report by the Dept. of Health and Human Services Office of Inspector General.
The study also found that foreign sites did not have the inspections that domestic ones did. The FDA inspected clinical investigators at less than 0.7% of foreign clinical trial sites compared with 1.9% for domestic sites.
The report comes as critics have raised concerns that foreign trials, particularly those in developing countries, may not provide results generalizable to the U.S. population. Medical ethicists also have questioned whether local regulatory bodies and institutional review boards adequately monitor clinical trials to protect the rights and welfare of subjects and to ensure data integrity.
With reliance on foreign clinical trials expected to grow, the report recommended that the FDA should:
■Require standardized electronic clinical trial data and create an internal database.
■Monitor trends in foreign clinical trials not conducted under Investigational New Drug applications and, if necessary, take steps to encourage sponsors to file INDs.
■Continue to explore ways to expand oversight of foreign clinical trials, including developing inspectional agreements with foreign regulatory bodies, inspecting clinical trials in more countries and looking to implement new oversight models.
Overall, the FDA agreed with the OIG's recommendations.
"For each OIG recommendation, the agency either has ongoing efforts that will address the recommendation or has initiated development of new procedures that will incorporate the recommendation," the FDA wrote in response to a draft of the OIG's report.
The FDA said it has long recognized the importance of data from clinical trials conducted outside the U.S., as long as the studies meet regulatory standards and yield results applicable to American patients. But the agency said increasing clinical trial globalization has presented challenges.
"Resource constraints limit the number of foreign clinical trial site inspections that can be conducted," the FDA said. "In addition, inspections are usually conducted after a clinical trial is completed, too late to fix any problems."
The Assn. of Clinical Research Organizations, which represents companies that focus on clinical research, said in a statement that it supports the recommendations.
Pharmaceutical Research and Manufacturers of America Senior Vice President Ken Johnson said in a statement, "Is it ethical to conduct such studies outside of the U.S.? In a word: Yes. ... Regardless of the location, however, companies seeking U.S. approval must maintain the FDA's high standards for conducting the trial."
"For instance, any related trials conducted outside the U.S. must comply with FDA requirements covering good clinical practices, in addition to meeting the requirements mandated in these important emerging markets."
Source
By Tanya Albert Henry, amednews correspondent. Posted July 19, 2010.
More than half of clinical trial subjects and sites for drugs and biologics were located outside the United States in fiscal 2008, a new study said. And 80% of the drug and biologic marketing applications that the Food and Drug Administration approved contained foreign clinical trial data.
Western Europe accounted for 58% of subjects enrolled at foreign sites and 60% of the foreign sites. Central and South America had a significant number, including the highest average number of subjects per site compared to other foreign regions, according to a June report by the Dept. of Health and Human Services Office of Inspector General.
The study also found that foreign sites did not have the inspections that domestic ones did. The FDA inspected clinical investigators at less than 0.7% of foreign clinical trial sites compared with 1.9% for domestic sites.
The report comes as critics have raised concerns that foreign trials, particularly those in developing countries, may not provide results generalizable to the U.S. population. Medical ethicists also have questioned whether local regulatory bodies and institutional review boards adequately monitor clinical trials to protect the rights and welfare of subjects and to ensure data integrity.
With reliance on foreign clinical trials expected to grow, the report recommended that the FDA should:
■Require standardized electronic clinical trial data and create an internal database.
■Monitor trends in foreign clinical trials not conducted under Investigational New Drug applications and, if necessary, take steps to encourage sponsors to file INDs.
■Continue to explore ways to expand oversight of foreign clinical trials, including developing inspectional agreements with foreign regulatory bodies, inspecting clinical trials in more countries and looking to implement new oversight models.
Overall, the FDA agreed with the OIG's recommendations.
"For each OIG recommendation, the agency either has ongoing efforts that will address the recommendation or has initiated development of new procedures that will incorporate the recommendation," the FDA wrote in response to a draft of the OIG's report.
The FDA said it has long recognized the importance of data from clinical trials conducted outside the U.S., as long as the studies meet regulatory standards and yield results applicable to American patients. But the agency said increasing clinical trial globalization has presented challenges.
"Resource constraints limit the number of foreign clinical trial site inspections that can be conducted," the FDA said. "In addition, inspections are usually conducted after a clinical trial is completed, too late to fix any problems."
The Assn. of Clinical Research Organizations, which represents companies that focus on clinical research, said in a statement that it supports the recommendations.
Pharmaceutical Research and Manufacturers of America Senior Vice President Ken Johnson said in a statement, "Is it ethical to conduct such studies outside of the U.S.? In a word: Yes. ... Regardless of the location, however, companies seeking U.S. approval must maintain the FDA's high standards for conducting the trial."
"For instance, any related trials conducted outside the U.S. must comply with FDA requirements covering good clinical practices, in addition to meeting the requirements mandated in these important emerging markets."
Source
July 18, 2010
Making Sense of Hepatitis C Research and Medical Literature
• Foreword
A newspaper headline states, “New Treatment Discovered for Hepatitis C.” An Internet site claims “more patients responded to drug A than drug B.” Your doctor prescribes a new medication for you and there are nearly 50 side effects listed for it. You attend a hepatitis C conference and each drug company tells you why their drug is better – all backed by research.
How do you know what is true? More specifically, what is true for you? If you do not have a research background, it may be difficult to understand statistics or scientific language. However, research is a bridge between disease and health. Your ability to cross that bridge may affect your future.
As you learn to live with HCV, you will make numerous decisions. These will include lifestyle, HCV management, and treatment choices. Your medical providers will advise you, but in the end, you decide what is right for you. Informed decisions likely lead to better outcomes.
How does someone living with HCV become informed? It takes education,curiosity, and patience. There are simple tools to help you wade through even the most complicated research. The purpose of this guide is to educate. The fact that you are reading this shows that you have curiosity. Add in some patience and the rest will fall into place. This guide will not turn you into an HCV expert. However, it will help you strengthen your skills in the area you are already an expert in – your own health.
Although HCV has been around a long time, knowledge about it is relatively new. Before it was accurately identified, it was called non-A, non-B hepatitis. In 1989, Michael Houghton and colleagues were able to isolate the virus, and non-A, non-B hepatitis was renamed hepatitis C.
Treatment for chronic HCV infection is a fairly new development. Therapy for chronic hepatitis C became available in 1991, with the Food and Drug Administration’s (FDA) approval of interferon alfa. This is a genetically engineered synthetic interferon designed to mimic the body’s natural interferon. Even though scientists do not understand completely how interferons work, they believe that one of their functions is to interfere with the production of new viruses, known as viral replication.
Before the 1990’s ended, there was another advance in HCV treatment. By adding ribavirin to interferon, treatment success rates improved. Although not fully understood, ribavirin weakens HCV, making it harder to multiply. Ribavirin must be used with interferon in order to be effective.
The most significant HCV treatment advance occurred in 2001 with the approval of pegylated interferon (peginterferon). Pegylation is a process that uses polyethylene glycol to coat a protein in order to strengthen and extend its activity in the body. The use of peginterferon plus ribavirin boosted treatment success rates to roughly 50-50.
These medical advances are only the beginning. Our understanding of HCV, and how to treat it, is growing rapidly. New therapies and variations using existing medications have raised the level of hope for the future for millions of people worldwide.
Evidence-based medicine is the practice of using solid research in order to formulate treatment recommendations.
Scientific study tries to answer questions about how to treat a disease. Clinical research, research studies, and clinical trials are similar terms that describe the procedure to answer these questions. A trial is a study designed to answer specific questions about a potential new therapy or new uses of an established therapy, as in “off-label” use. The specific questions most often examined are about safety and efficacy. Safety refers to the drug’s toxicity or side effects. Efficacy refers to the drug’s effectiveness, i.e., if it works.
Drug research usually tests laboratory animals before humans. Laboratory animals are protected by strict regulations.
Clinical trials follow a protocol, a set of procedures that are written in great detail, like a recipe. The protocol states how the clinical trial will be conducted, who can participate, how the drug will be administered, and how the participants will be monitored. The protocol is reviewed by many people, including the sponsor of the study, the participating investigators, members of the local Institutional Review Board (IRB), and, in some circumstances, representatives of the Food and Drug Administration (FDA). A protocol is required whether the study is for new drugs or for new uses of drugs that are already FDA-approved. The trial cannot begin until everyone approves the design.
Although heavily regulated, clinical trials are not necessarily good for all patients. Protocols vary in quality, objectives, and level of risk. To judge whether a clinical trial is appropriate for you, you need to examine it closely. This guide will suggest ways to do this.
• Phases of Clinical Trials
In order to find treatments for chronic hepatitis C that are safe and effective, new drugs, including interferons, must undergo rigorous testing. Drug research involves many stages. Much of the knowledge about drugs is derived from initial laboratory research in animals. Animals are used during the drug development phase, primarily to confirm lack of toxicity. If laboratory tests show that a drug has potential therapeutic value without major toxicity, it may advance to the next stage. The next step involves an extensive process of applying to the FDA for permission to proceed. After careful review of the preliminary data, if the FDA gives its approval, then drug testing – clinical trials – can begin on humans.
Clinical trials may have up to four phases. The initial introduction of an investigational new drug using humans occurs in Phase I. The subjects in this phase are usually healthy volunteers (usually 20 to 80 subjects). Sometimes the subjects are those with the disease that is being studied. The goals of a Phase I trial are to evaluate safety and tolerability (i.e., lack of major side effects) as well as the dosage range. This is determined by testing a range of doses (called a dose-ranging trial). Study participants initially receive a low dose of the drug; this is gradually increased as long as the drug appears to be safe. Phase I studies may provide early indications of the drug’s effectiveness, but whether or not a drug works is the primary focus of Phase II and Phase III studies.
In Phase II trials, clinical studies are conducted using patients with the disease for which the drug is being tested. The goal of this phase is to obtain preliminary data on the effectiveness (also known as efficacy) of the test drug. This phase also allows further collection of data on the common short-term side effects and risks associated with the drug. A relatively small number of participants enroll in Phase II studies (100 to 300 subjects).
After confirming preliminary evidence of effectiveness in Phase II studies, the goal of Phase II studies is to gain additional information on effectiveness and safety. In this phase, several hundred to several thousand subjects receive the test drug. In Phase III studies, the new drug is often compared to current standard therapy.
After the drug is approved and marketed, the FDA may require a company to obtain more information about the drug. These studies occur as Phase IV trials. Examples are the safety and efficacy of varying doses, how the drug interacts with other drugs, or how it works in people with other diseases. Phase IV trials may include small or large numbers of subjects and may reveal uncommon side effects that are too rare to show up in Phase II or III studies.
• Drug Development: Timeline and Cost
Before a drug is approved for marketing, it is called an investigational new drug (IND). The total time it takes to bring a drug to market can vary. According to the FDA, the preclinical laboratory phase ranges from 1 to 3 years with an average of 18 months. The length of time an investigational drug is in clinical trials ranges from 2 – 10 years, averaging 5 years. The FDA review and approval process may take up to 7 years, while averaging 2 years. The average total time from bench to market is almost 9 years. According to the FDA, only one in 1,000 compounds makes it from the laboratory to human testing, and only one in five of these receives FDA approval for marketing (http://www.fda.gov/).
The cost of conducting a clinical trial is enormous. A price tag of several hundred million dollars is common. The total price from the lab to the pharmacy may be over a billion dollars. Funding for a trial can come from various sources, with the majority sponsored by pharmaceutical companies. In addition, the U.S. federal government provides funding through the National Institutes of Health. Investigators may also receive research money from the public, from industry and from other private sources.
• Types of Studies
Clinical observations, also known as anecdotal evidence or case studies, are the collection of information based on clinicians’ observations. A case study of one or only a few patients does not carry much weight, because the total number of patients is too small to obtain statistically significant results, and there may be bias in the selection of patients reported.
The most reliable research results come from a prospective study. Simply put, prospective studies look ahead with the intention of collecting data. These studies are carefully planned and conducted in a standard manner with well-defined patient populations and treatment protocols. The number of participants is known as the sample size. The larger the sample size, the more valid the results.
Prospective studies are more reliable when subjects do not know if they are receiving the study drug or a placebo (an inactive substance). This is called a blind study. The most reliable condition is when neither the subjects nor the investigators know whether the study drug or placebo is being administered (a double-blind study). Although researchers and patients try to remain objective, they may unknowingly influence the results. For instance, if a nurse knew you were on a study drug, he or she might unintentionally treat you differently than if it was thought you were on the placebo. As a patient, you might act differently if you thought you were receiving a placebo.
Retrospective studies look at past data. Retrospective studies are used to gain understanding for situations that have already happened. If someone wanted to know what the risk factors were for people with HCV, they would conduct a retrospective study. Retrospective studies are great for gaining understanding but they are not prospective studies since the outcome is already known. Even the best scientists can be biased, so most drug studies are prospective and double-blinded.
If a particular topic interests you, look at an article’s reference section to find more articles on that subject.
Head-to-head clinical trials compare two or more drugs or treatments. These studies are good ways to compare medications to see if one is more effective. A true head-to-head trial maintains identical factors except for the one variable you are studying. Unfortunately, even the most carefully designed studies may be flawed, particularly if the researcher favors one of the drugs.
Medical literature and research articles can be hard to understand. Be patient – with practice it will get easier.
The most comprehensive information comes from research articles published in medical journals after peer-review. Peer-review means that the paper is reviewed by two or three independent physicians or investigators with no relationship to the study authors or sponsors. In addition, the editor and associate editors of the journal also carefully review the research study methods and conclusions.
When learning how to read medical literature, start with peer-reviewed articles in well-known medical publications, such as Hepatology, the American Journal of Medicine or the New England Journal of Medicine. When published in prestigious journals, these peer-reviewed studies carry great weight.
It may be helpful to have a medical dictionary at hand. The Internet is a good place to find definitions.
Journal articles follow similar formats. Most articles start with an abstract. This is a brief summary of important points of the research article. The larger article begins with an Introduction or Background. This is followed by the Methods section, the Results or Findings section and the Discussion or Findings section. References are listed at the end.
Read with a critical mind. Before you begin, formulate some questions that you want answered. What are you looking for? Does the research discuss people who are similar to you? For instance, if you are 65 years old and everyone in the study was under 40, then perhaps the research does not apply to you. In short, look at what was studied, who was studied, how they were studied, and what the conclusions were.
First, read the abstract. The abstract may tell you if the article applies to you. If only men were studied, women may want to look for studies that included both sexes. The abstract is a quick way to decide if you want to read the rest of the article.
When reading a medical article, ask: What was studied? Who was studied? How were they studied? What were the conclusions?
The introduction or background section describes what is known and unknown about the topic. Every fact in this section comes from another source. This is known as a citation. If you want to know where the citation came from, look for a number or name alongside the text. This will match a name or number in the reference section listing the source of the information.
The methods section describes the design of the study. It tells you who and what was studied, how it was done, and how the results were evaluated. Here are important points to explore:
a. How many subjects were enrolled in the study? Larger studies carry more weight.
b. Who participated in the research and how were they chosen? Weremthey evenly matched by age, gender, race, genotype, weight, viral load, degree of liver damage, general health and other important variables?
c. Was the clinical trial randomized and blinded to prevent bias? (Subjects are selected randomly to a particular study group to receive the test drug, a standard of care drug or a placebo.) The double-blind, randomized control trial is the most desirable design.
d. What kind of study was it, i.e., prospective, retrospective?
e. How did the researchers test their theory and what tools did they use? Were they using sensitive diagnostic tools?
f. Was the study designed to compare one drug against another drug, or against the current standard of care? Was the dose of medication appropriate in both groups? Was there only one variable or were there many?
The results or findings section reports on the outcome of the study. It should break down the information by overall results and then by patient characteristics and medication dose. The results should also report the statistical significance – an indicator of how well the drug will work under the same circumstances in a different setting. This is usually reported as a p-value. A p-value of < 0.05 (less than 5%) is considered statistically significant. P=0.05 means that there is a 95% chance the drug will work and a 5% chance that it will not.
Research articles end with some sort of conclusion, summary, or recommendation. This is the bottom line. The author(s) state what they found and what they did not find. The strengths and weaknesses of the trial may be discussed. Not coming to a conclusion is just as important as coming to one. The conclusion should be consistent with the results. If you are short on time, you may be tempted to read only the conclusion. This is fine if the research is good and applies to you. However, it is best to read the entire article – even if you do not understand it. The more you practice reading medical literature, the more you will be able to understand the information presented. Use a critical mind when trying to interpret scientific data or any other source of information. Do not be afraid to ask questions – most medical professionals welcome questions and the involvement of patients in their medical care and management.
• Making Sense of Medical Literature
Reading medical literature is only a small part of educating yourself. Making sense of what you read is the important part. To do this, you need to apply critical thinking. Critical thinking is a process of gathering information, analyzing it and evaluating it.
Critical thinkers try to determine if information is fact. They look closely at research results to see if they are valid. Do the final numbers include all of the participants in the study, or only the ones who stayed in the study for its entire length? If a study analysis includes all of the data from all of the participants who were originally enrolled, it is an intent-to-treat analysis. However, if a study analysis excludes participants who dropped out early due to side effects or for some other reason, it is an as-treated analysis.
Don’t believe everything you read. Learn to be a critical thinker.
Example:
Study #1 uses an intent-to-treat analysis. The final report states that 50% of the participants were cured. Looking at the data, you noticed that 100 people enrolled in the study. 25 people dropped out because of side effects; another 25 were not cured. The remaining 50 participants were cured, which equals 50%.
Study #2 claimed their drug was better because they had a 67% cure rate. However, this study used an as-treated analysis. They also started with 100 participants and had 25 drop out because of side effects. However, they analyzed the data based on the remaining participants. By stating that 50 out of 75 were cured, it looks like they had better results. In fact, they had the same results.
An important aspect to consider when evaluating studies is how the study was conducted.
Example:
Brand A is the only available drug. Brand A’s label directed everyone to receive 100 mgs. As time passed, physicians noticed that Brand A did not help people who were overweight. They did some studies and learned that overweight people needed higher doses. The FDA allows physicians to do this even if the drug’s label does not specifiy it.
Along comes Brand B. In its clinical trials, the doses for Brand B were determined based on peoples’ weights. Naturally, Brand B wants to prove that it is better than Brand A. Brand B conducts a clinical trial comparing participants taking each drug – a head-to-head study. However, the study design is flawed in favor of Brand B. Everyone taking Brand A will get the dose that is on the label – regardless of their weight. Everyone on Brand B will get a dose that matches his or her weight. If there are many heavy people in the study, then those getting Brand B will get more medication.
When looking at research results, always compare apples to apples and oranges to oranges.
It is important to learn if the study results apply to you. For example, if a drug was studied using middle-aged men, is it also safe and effective for a 20-year-old woman? Studies of new drugs usually involve a population of similar people (homogeneous population). However, even a study that uses a homogenous population needs to be examined critically. For instance, what does it mean if a report claims that 50% responded to an HCV therapy? If everyone in the study had your genotype, then the results may apply to you. However, if everyone had a different genotype, then you cannot apply the results to your situation.
There are other apples-to-apples issues when analyzing and comparing study results. Let us look at two studies. Both have the same number of participants, all the same gender, age, genotype, viral load, ethnic background, and liver biopsy results. However, Study #1 enrolled subjects with only one disease – HCV. Study #2 enrolled subjects with histories of mild depression, heart disease, and so on. It would be no surprise if Study #1 had better outcomes. Be sure to compare yourself with those who are similar to you before applying results to your situation.
Most studies have historically used the p-value to indicate whether the results of a study are significant, or clinically important. In other words, what is the chance that treatment with a new drug has no effect (the so-called null hypothesis) versus the chance that it has a positive effect? Based on tradition, a p-value of < 0.05 is used as the determination of statistical significance, or a positive result. What this means in a general sense is that a p-value of < 0.05 indicates that there is a 95% chance that the drug really works (true positive) and only a 5% chance that it does not (false positive). A p-value of < 0.01 is considered “highly significant.”
The proper use of statistics is more complicated than the above explanation. Some studies involve thousands of patients, while others involve relatively few patients. A false positive error (also called type I, or α error) using p < 0.05 means that the drug may not really work AND is greater in smaller studies. Studies with more participants are said to have a higher power. Studies must be large enough to avoid concluding that the effectiveness of a new treatment is the same as that of the standard treatment or placebo (i.e., a false negative result, also called a type II, or β error) when it is in reality better. What if the results of a study of a new versus the standard drug are deemed negative because it results in a p-value of, for example, 0.1 or 0.06? This is just above the arbitrary 0.05 level, below which studies are considered significant by convention. Is this truly a negative result? More sophisticated statistical analysis (using a technique called confidence limits or intervals), or repeated and larger studies, can sometimes help determine the “truth” about a new drug.
• Understanding Surveys
Sometimes information is conveyed by way of surveys. Surveys are not evidence-based. Survey results may be misleading and should not be used to make medical decisions. However, surveys and polls may promote a product or an opinion, so knowing how to evaluate them is important.
Who is funding the web site from which you get your information? Advertising on a web site tells you who, but even websites without ads may be paid for by commercial interests.
How a question is asked may influence the outcome. For example, Alice takes a poll that asks, “Should we invest more money into access to better healthcare?” Most people will probably favor this. Alice’s opponent Betty asks, “Should we raise taxes to fund big government by passing a healthcare funding bill?” Now people are likely to oppose this. However, both Alice and Betty will use the survey results to support their positions.
The survey sample size is a significant factor that may be misleading. For instance, if two people are asked their opinion about Brand X and they both liked it, then it looks like 100% of the people surveyed liked Brand X. However if two more people are surveyed and their opinion differs from the first two, then that number drops to 50%.
There is another way to manipulate statistics using sample size and perseverence. Brand A wants to be the best and hopes to claim that at least four out of five doctors recommend their product. They ask the opinions of five doctors. If only one endorses Brand A, they ask five more doctors. If only three of them recommend it, they keep asking until they get four out of five. The surveyor is under no obligation to tell you that they asked 100 doctors before finding the desired response.
Look for web sites that end in .gov or .org rather than .com
Watch for bias. Even well-meaning researchers are biased. Suppose a researcher wants to prove his/her belief that HCV patients who are optimists fare better during treatment than pessimists do. This may affect the outcome before the study even begins. The researcher suspects the answer before the study starts and is looking for proof to support that belief. In subtle ways, this prejudice may influence the study design, conduct, and interpretation of data. The best way to conduct a study is with no preconceived notion of the outcome.
• The Internet as a Source
The Internet is a valuable tool. However, like any tool, one needs to know how to use it well. The following are some suggestions for how to use the Internet more effectively:
• Find out if the information comes from a reliable source. Information from independent and not-for-profit sources, particularly from the U.S. federal government (e.g., National Institutes of Health (NIH), FDA), a general medical society (e.g., American Medical Association) or specialty or disease society (e.g., American Association for the Study of Liver Diseases) is likely to be reliable. Commercial sources (e.g., pharmaceutical companies) may be scientifically accurate, but may emphasize the positive aspects of a drug for marketing purposes.
• Look for information that includes author names, medical affiliations, references, and publication dates.
• Information provided in chat rooms and discussion forums is frequently anecdotal and based on individual experiences, which often cannot be generalized to all people with the same condition.
• Question what you read. Does the research stand up to careful scrutiny?
• Do not panic. It is easy to be overwhelmed and frightened by what appears to be “bad news.” Get more information before overreacting.
• Never use the Internet as a substitute for medical care.
• The Bottom Line
Most of us rely on numbers. Numbers seem black and white. After all, two plus two equals four. However, the reliability of numbers is only as good as the humans interpreting them. So, how do we know what to trust? How can we separate fact from fiction? Here are some suggestions:
1. Look at the source. If statistics are used for commercial or political purposes, the numbers may have been spun. If the numbers come from a reliable medical journal, such as Hepatology, New England Journal of Medicine, or Lancet, it is likely that these have stood up to scrutiny.
2. Compare apples to apples. If the subjects in a study were all Caucasian males over the age of 40, then the information may not apply to a 20-year-old African American female.
3. Use critical thinking. Ask questions. Assume nothing. Challenge what you read.
4. Check the source of funding for the research. It is not objective research if the data for the product comes solely from the manufacturer. Data needs to be verified independently by more than one source before it can be considered reliable.
5. Do not let emotions get in the way of facts. It is disturbing to read about HCV, but the majority of us will die with HCV and not of HCV.
6. Get a reliable second opinion to confirm your understanding of the research.
7. Seek opinions from others who respect evidence-based medicine. They may have already found the information you are seeking.
8. Keep an open mind. Do not form an opinion and look for the facts to conform to your opinion. This means you are biased too.
Abstract – a brief summary of important points of a research article or other text.
Adverse event – an undesired action or effect of an experimental treatment.
Anecdotal evidence – the collection of information based on clinicians’ observations.
Antibody – a protein produced by the immune system when a foreign substance enters the body. The presence of antibodies is an indicator of a past or possibly current infection. HCV antibodies are written as anti-HCV. The test for anti-HCV is often the first step in diagnosing chronic HCV infection. A positive anti-HCV test must be followed by other laboratory tests in order to confirm the diagnosis. The antibody test alone is not sufficient to make a diagnosis of chronic HCV infection.
Biopsy – a procedure in which a sample of cells or tissue is taken to examine in a laboratory. In HCV, liver biopsies are used to monitor the health of the liver.
Blind or double-blind study – this refers to whether or not the research team or study participants know whether the participants are receiving a placebo or the experimental drug. In a blinded study, the participants do not know if they are receiving the test drug or the placebo. In a double-blind study, neither the participants nor the researchers who administer the treatment know who is receiving the experimental drug or the placebo. In the case of medical necessity, a study can be unblinded to reveal who is and is not receiving the experimental treatment.
Citation – refers to the source of the information
Combination therapy – two or more drugs that are used in combination with each other in order to improve the effectiveness of treatment. When applied to HCV treatment, this term most often refers to the use of interferon plus ribavirin.
Control group – the group of participants in a clinical trial who receive the current standard treatment or no active treatment, and not the new drug under study.
Efficacy – refers to the drug’s effectiveness, i.e., if it works.
Endpoints – The outcomes used to judge the effectiveness of the treatments.
Evidence-based medicine – Used by medical providers, this is the practice of using solid research in order to formulate treatment recommendations.
Exclusion criteria – conditions that disqualify someone from participating in a clinical trial.
Experimental group – the group of study participants who receive the new experimental treatment.
FDA – abbreviation for the Food and Drug Administration. This U.S. federal government agency has many functions. It is responsible for granting or denying approval for drugs to be sold to the public.
Genotype – genetic variation in the structure of a virus. HCV has six major genotypes, designated by the numbers 1 through 6. There are also many subtypes, e.g., 1a, 1b, 2a, etc. In the U.S., genotype 1 is predominant (approximately 70-75% of patients).
Half-life – the period of time it takes for the concentration of a drug to decrease to half its original concentration in the blood.
HCV RNA – the genetic material of the hepatitis C virus. HCV is a singlestranded ribonucleic acid (RNA) virus.
HCV polymerase inhibitor – an agent that inhibits HCV replication by interfering with the virus’ polymerase enzyme.
HCV protease inhibitor – an agent that inhibits HCV replication by interfering with the virus’ protease enzyme.
Inclusion criteria – conditions that must be met in order to be eligible for a clinical trial.
Institutional review board (IRB) – an IRB is a group that has been formally designated to review and monitor research involving human subjects. It has the authority to approve, require modifications in, or disapprove research. The purpose of IRB review is to protect the rights and welfare of humans participating in research.
Interferon-alfa – a naturally occurring protein in the human body produced by the immune system. Interferon interferes with viral replication. Genetically engineered products based on the natural protein have been developed by several pharmaceutical companies, and are approved for the treatment of chronic HCV infection.
Investigational new drug (IND) – a drug that the FDA allows to be used in human clinical trials in order to gain information for evaluation by the FDA, usually for approval for commercial marketing.
Investigator – a clinical researcher who is involved with a clinical trial protocol and its implementation. The Principal Investigator is ultimately responsible for the conduct of the trial.
Off-label – use of an FDA-approved drug for an indication other than that for which it was approved.
Open-label trial – a clinical trial in which doctors and participants know which drug is being administered.
P-value – a measure of probability that is reported with clinical trial results. The p-value indicates the likelihood the results obtained are not due to chance alone. Traditionally, a p-value of less than .05 is considered statistically significant or not likely due to chance alone.
Peer review – review of a clinical trial by experts who were not associated with the research. Looks at scientific merit, participant safety, and ethical considerations.
Pegylated interferon (PegIntron™, Pegasys®) – a form of interferon that has a long half-life in the body and be can be injected less often (typically a week). Pegylated interferon is approved for the treatment of HCV.
Placebo – a pill (capsule, liquid, or injection) that contains an inactive substance. It is compared to the experimental drug in placebocontrolled clinical trials.
Protocol – a written document that states the guidelines of how a clinical trial will be conducted. A protocol includes all of the details of the study, including who can participate, how the study drug will be administered, drug side effects, and risks.
Randomization – the process of randomly assigning study participants to either the control (standard treatment or no treatment) or experimental (new drug) group.
Ribavirin – an antiviral medication that is used in combination with an interferon product for treatment of chronic HCV infection.
Risk/benefit ratio – a measurement used to evaluate whether potential benefits outweigh potential risks.
Safety – refers to the drug’s toxicity or side effects.
Single-blinded study – this refers to a study in which the participants do not know if they are receiving the test substance or the placebo. See blind/double-blind study.
Standard of care – the level of care that all persons with a particular illness should receive; the level below which care would be considered substandard.
Standard treatment – the best or most widely used currently available treatment.
Study arm – clinical trials usually compare the responses of two or more groups of subjects (e.g., control and treatment groups). If a study has more than one treatment group (for example, receiving varying dosages of a drug), the different groups are called study arms.
Sponsor – the sponsor of new drug studies is typically a drug or biologic manufacturer. Other potential sponsors include a university or independent foundation supporting the research.
Subject – a volunteer participant in a clinical trial.
Treatment-naïve – a person who has not had prior treatment for a particular condition.
Viral load – the amount of virus (i.e., the HCV RNA level) that can be measured, usually in the blood.
Viral replication – the ability of a virus to reproduce copies of itself.
Virus – a microscopic infectious particle that invades a living organism and makes copies of itself (viral replication).
A newspaper headline states, “New Treatment Discovered for Hepatitis C.” An Internet site claims “more patients responded to drug A than drug B.” Your doctor prescribes a new medication for you and there are nearly 50 side effects listed for it. You attend a hepatitis C conference and each drug company tells you why their drug is better – all backed by research.
How do you know what is true? More specifically, what is true for you? If you do not have a research background, it may be difficult to understand statistics or scientific language. However, research is a bridge between disease and health. Your ability to cross that bridge may affect your future.
As you learn to live with HCV, you will make numerous decisions. These will include lifestyle, HCV management, and treatment choices. Your medical providers will advise you, but in the end, you decide what is right for you. Informed decisions likely lead to better outcomes.
How does someone living with HCV become informed? It takes education,curiosity, and patience. There are simple tools to help you wade through even the most complicated research. The purpose of this guide is to educate. The fact that you are reading this shows that you have curiosity. Add in some patience and the rest will fall into place. This guide will not turn you into an HCV expert. However, it will help you strengthen your skills in the area you are already an expert in – your own health.
Hepatitis C
Hepatitis C is the most common blood-borne virus in the United States (http://www.cdc.gov/). More than 4 million Americans have been infected with the hepatitis C virus (HCV) at some time in the past, and about 3.2 million have not recovered and have chronic infection.
Although HCV has been around a long time, knowledge about it is relatively new. Before it was accurately identified, it was called non-A, non-B hepatitis. In 1989, Michael Houghton and colleagues were able to isolate the virus, and non-A, non-B hepatitis was renamed hepatitis C.
Treatment for chronic HCV infection is a fairly new development. Therapy for chronic hepatitis C became available in 1991, with the Food and Drug Administration’s (FDA) approval of interferon alfa. This is a genetically engineered synthetic interferon designed to mimic the body’s natural interferon. Even though scientists do not understand completely how interferons work, they believe that one of their functions is to interfere with the production of new viruses, known as viral replication.
Before the 1990’s ended, there was another advance in HCV treatment. By adding ribavirin to interferon, treatment success rates improved. Although not fully understood, ribavirin weakens HCV, making it harder to multiply. Ribavirin must be used with interferon in order to be effective.
The most significant HCV treatment advance occurred in 2001 with the approval of pegylated interferon (peginterferon). Pegylation is a process that uses polyethylene glycol to coat a protein in order to strengthen and extend its activity in the body. The use of peginterferon plus ribavirin boosted treatment success rates to roughly 50-50.
These medical advances are only the beginning. Our understanding of HCV, and how to treat it, is growing rapidly. New therapies and variations using existing medications have raised the level of hope for the future for millions of people worldwide.
Evidence-based medicine is the practice of using solid research in order to formulate treatment recommendations.
Clinical Research
Every day, medical providers make many patient-management decisions. Each decision involves weighing benefits and risks and determining the course of action judged to be in a patient’s best interest. Providers use their clinical expertise along with medical literature to guide these decisions. An important question is, upon what evidence is a treatment recommendation made? This is evidence-based medicine. The best evidence comes from solid, rigorously reviewed research.
Scientific study tries to answer questions about how to treat a disease. Clinical research, research studies, and clinical trials are similar terms that describe the procedure to answer these questions. A trial is a study designed to answer specific questions about a potential new therapy or new uses of an established therapy, as in “off-label” use. The specific questions most often examined are about safety and efficacy. Safety refers to the drug’s toxicity or side effects. Efficacy refers to the drug’s effectiveness, i.e., if it works.
Drug research usually tests laboratory animals before humans. Laboratory animals are protected by strict regulations.
Clinical trials follow a protocol, a set of procedures that are written in great detail, like a recipe. The protocol states how the clinical trial will be conducted, who can participate, how the drug will be administered, and how the participants will be monitored. The protocol is reviewed by many people, including the sponsor of the study, the participating investigators, members of the local Institutional Review Board (IRB), and, in some circumstances, representatives of the Food and Drug Administration (FDA). A protocol is required whether the study is for new drugs or for new uses of drugs that are already FDA-approved. The trial cannot begin until everyone approves the design.
Although heavily regulated, clinical trials are not necessarily good for all patients. Protocols vary in quality, objectives, and level of risk. To judge whether a clinical trial is appropriate for you, you need to examine it closely. This guide will suggest ways to do this.
• Phases of Clinical Trials
In order to find treatments for chronic hepatitis C that are safe and effective, new drugs, including interferons, must undergo rigorous testing. Drug research involves many stages. Much of the knowledge about drugs is derived from initial laboratory research in animals. Animals are used during the drug development phase, primarily to confirm lack of toxicity. If laboratory tests show that a drug has potential therapeutic value without major toxicity, it may advance to the next stage. The next step involves an extensive process of applying to the FDA for permission to proceed. After careful review of the preliminary data, if the FDA gives its approval, then drug testing – clinical trials – can begin on humans.
Clinical trials may have up to four phases. The initial introduction of an investigational new drug using humans occurs in Phase I. The subjects in this phase are usually healthy volunteers (usually 20 to 80 subjects). Sometimes the subjects are those with the disease that is being studied. The goals of a Phase I trial are to evaluate safety and tolerability (i.e., lack of major side effects) as well as the dosage range. This is determined by testing a range of doses (called a dose-ranging trial). Study participants initially receive a low dose of the drug; this is gradually increased as long as the drug appears to be safe. Phase I studies may provide early indications of the drug’s effectiveness, but whether or not a drug works is the primary focus of Phase II and Phase III studies.
In Phase II trials, clinical studies are conducted using patients with the disease for which the drug is being tested. The goal of this phase is to obtain preliminary data on the effectiveness (also known as efficacy) of the test drug. This phase also allows further collection of data on the common short-term side effects and risks associated with the drug. A relatively small number of participants enroll in Phase II studies (100 to 300 subjects).
After confirming preliminary evidence of effectiveness in Phase II studies, the goal of Phase II studies is to gain additional information on effectiveness and safety. In this phase, several hundred to several thousand subjects receive the test drug. In Phase III studies, the new drug is often compared to current standard therapy.
After the drug is approved and marketed, the FDA may require a company to obtain more information about the drug. These studies occur as Phase IV trials. Examples are the safety and efficacy of varying doses, how the drug interacts with other drugs, or how it works in people with other diseases. Phase IV trials may include small or large numbers of subjects and may reveal uncommon side effects that are too rare to show up in Phase II or III studies.
• Drug Development: Timeline and Cost
Before a drug is approved for marketing, it is called an investigational new drug (IND). The total time it takes to bring a drug to market can vary. According to the FDA, the preclinical laboratory phase ranges from 1 to 3 years with an average of 18 months. The length of time an investigational drug is in clinical trials ranges from 2 – 10 years, averaging 5 years. The FDA review and approval process may take up to 7 years, while averaging 2 years. The average total time from bench to market is almost 9 years. According to the FDA, only one in 1,000 compounds makes it from the laboratory to human testing, and only one in five of these receives FDA approval for marketing (http://www.fda.gov/).
The cost of conducting a clinical trial is enormous. A price tag of several hundred million dollars is common. The total price from the lab to the pharmacy may be over a billion dollars. Funding for a trial can come from various sources, with the majority sponsored by pharmaceutical companies. In addition, the U.S. federal government provides funding through the National Institutes of Health. Investigators may also receive research money from the public, from industry and from other private sources.
• Types of Studies
Clinical observations, also known as anecdotal evidence or case studies, are the collection of information based on clinicians’ observations. A case study of one or only a few patients does not carry much weight, because the total number of patients is too small to obtain statistically significant results, and there may be bias in the selection of patients reported.
The most reliable research results come from a prospective study. Simply put, prospective studies look ahead with the intention of collecting data. These studies are carefully planned and conducted in a standard manner with well-defined patient populations and treatment protocols. The number of participants is known as the sample size. The larger the sample size, the more valid the results.
Prospective studies are more reliable when subjects do not know if they are receiving the study drug or a placebo (an inactive substance). This is called a blind study. The most reliable condition is when neither the subjects nor the investigators know whether the study drug or placebo is being administered (a double-blind study). Although researchers and patients try to remain objective, they may unknowingly influence the results. For instance, if a nurse knew you were on a study drug, he or she might unintentionally treat you differently than if it was thought you were on the placebo. As a patient, you might act differently if you thought you were receiving a placebo.
Retrospective studies look at past data. Retrospective studies are used to gain understanding for situations that have already happened. If someone wanted to know what the risk factors were for people with HCV, they would conduct a retrospective study. Retrospective studies are great for gaining understanding but they are not prospective studies since the outcome is already known. Even the best scientists can be biased, so most drug studies are prospective and double-blinded.
If a particular topic interests you, look at an article’s reference section to find more articles on that subject.
Head-to-head clinical trials compare two or more drugs or treatments. These studies are good ways to compare medications to see if one is more effective. A true head-to-head trial maintains identical factors except for the one variable you are studying. Unfortunately, even the most carefully designed studies may be flawed, particularly if the researcher favors one of the drugs.
Medical literature and research articles can be hard to understand. Be patient – with practice it will get easier.
How to Read Medical Research Articles
The most comprehensive information comes from research articles published in medical journals after peer-review. Peer-review means that the paper is reviewed by two or three independent physicians or investigators with no relationship to the study authors or sponsors. In addition, the editor and associate editors of the journal also carefully review the research study methods and conclusions.
When learning how to read medical literature, start with peer-reviewed articles in well-known medical publications, such as Hepatology, the American Journal of Medicine or the New England Journal of Medicine. When published in prestigious journals, these peer-reviewed studies carry great weight.
It may be helpful to have a medical dictionary at hand. The Internet is a good place to find definitions.
Journal articles follow similar formats. Most articles start with an abstract. This is a brief summary of important points of the research article. The larger article begins with an Introduction or Background. This is followed by the Methods section, the Results or Findings section and the Discussion or Findings section. References are listed at the end.
Read with a critical mind. Before you begin, formulate some questions that you want answered. What are you looking for? Does the research discuss people who are similar to you? For instance, if you are 65 years old and everyone in the study was under 40, then perhaps the research does not apply to you. In short, look at what was studied, who was studied, how they were studied, and what the conclusions were.
First, read the abstract. The abstract may tell you if the article applies to you. If only men were studied, women may want to look for studies that included both sexes. The abstract is a quick way to decide if you want to read the rest of the article.
When reading a medical article, ask: What was studied? Who was studied? How were they studied? What were the conclusions?
The introduction or background section describes what is known and unknown about the topic. Every fact in this section comes from another source. This is known as a citation. If you want to know where the citation came from, look for a number or name alongside the text. This will match a name or number in the reference section listing the source of the information.
The methods section describes the design of the study. It tells you who and what was studied, how it was done, and how the results were evaluated. Here are important points to explore:
a. How many subjects were enrolled in the study? Larger studies carry more weight.
b. Who participated in the research and how were they chosen? Weremthey evenly matched by age, gender, race, genotype, weight, viral load, degree of liver damage, general health and other important variables?
c. Was the clinical trial randomized and blinded to prevent bias? (Subjects are selected randomly to a particular study group to receive the test drug, a standard of care drug or a placebo.) The double-blind, randomized control trial is the most desirable design.
d. What kind of study was it, i.e., prospective, retrospective?
e. How did the researchers test their theory and what tools did they use? Were they using sensitive diagnostic tools?
f. Was the study designed to compare one drug against another drug, or against the current standard of care? Was the dose of medication appropriate in both groups? Was there only one variable or were there many?
The results or findings section reports on the outcome of the study. It should break down the information by overall results and then by patient characteristics and medication dose. The results should also report the statistical significance – an indicator of how well the drug will work under the same circumstances in a different setting. This is usually reported as a p-value. A p-value of < 0.05 (less than 5%) is considered statistically significant. P=0.05 means that there is a 95% chance the drug will work and a 5% chance that it will not.
Research articles end with some sort of conclusion, summary, or recommendation. This is the bottom line. The author(s) state what they found and what they did not find. The strengths and weaknesses of the trial may be discussed. Not coming to a conclusion is just as important as coming to one. The conclusion should be consistent with the results. If you are short on time, you may be tempted to read only the conclusion. This is fine if the research is good and applies to you. However, it is best to read the entire article – even if you do not understand it. The more you practice reading medical literature, the more you will be able to understand the information presented. Use a critical mind when trying to interpret scientific data or any other source of information. Do not be afraid to ask questions – most medical professionals welcome questions and the involvement of patients in their medical care and management.
• Making Sense of Medical Literature
Reading medical literature is only a small part of educating yourself. Making sense of what you read is the important part. To do this, you need to apply critical thinking. Critical thinking is a process of gathering information, analyzing it and evaluating it.
Critical thinkers try to determine if information is fact. They look closely at research results to see if they are valid. Do the final numbers include all of the participants in the study, or only the ones who stayed in the study for its entire length? If a study analysis includes all of the data from all of the participants who were originally enrolled, it is an intent-to-treat analysis. However, if a study analysis excludes participants who dropped out early due to side effects or for some other reason, it is an as-treated analysis.
Don’t believe everything you read. Learn to be a critical thinker.
Example:
Study #1 uses an intent-to-treat analysis. The final report states that 50% of the participants were cured. Looking at the data, you noticed that 100 people enrolled in the study. 25 people dropped out because of side effects; another 25 were not cured. The remaining 50 participants were cured, which equals 50%.
Study #2 claimed their drug was better because they had a 67% cure rate. However, this study used an as-treated analysis. They also started with 100 participants and had 25 drop out because of side effects. However, they analyzed the data based on the remaining participants. By stating that 50 out of 75 were cured, it looks like they had better results. In fact, they had the same results.
An important aspect to consider when evaluating studies is how the study was conducted.
Example:
Brand A is the only available drug. Brand A’s label directed everyone to receive 100 mgs. As time passed, physicians noticed that Brand A did not help people who were overweight. They did some studies and learned that overweight people needed higher doses. The FDA allows physicians to do this even if the drug’s label does not specifiy it.
Along comes Brand B. In its clinical trials, the doses for Brand B were determined based on peoples’ weights. Naturally, Brand B wants to prove that it is better than Brand A. Brand B conducts a clinical trial comparing participants taking each drug – a head-to-head study. However, the study design is flawed in favor of Brand B. Everyone taking Brand A will get the dose that is on the label – regardless of their weight. Everyone on Brand B will get a dose that matches his or her weight. If there are many heavy people in the study, then those getting Brand B will get more medication.
When looking at research results, always compare apples to apples and oranges to oranges.
It is important to learn if the study results apply to you. For example, if a drug was studied using middle-aged men, is it also safe and effective for a 20-year-old woman? Studies of new drugs usually involve a population of similar people (homogeneous population). However, even a study that uses a homogenous population needs to be examined critically. For instance, what does it mean if a report claims that 50% responded to an HCV therapy? If everyone in the study had your genotype, then the results may apply to you. However, if everyone had a different genotype, then you cannot apply the results to your situation.
There are other apples-to-apples issues when analyzing and comparing study results. Let us look at two studies. Both have the same number of participants, all the same gender, age, genotype, viral load, ethnic background, and liver biopsy results. However, Study #1 enrolled subjects with only one disease – HCV. Study #2 enrolled subjects with histories of mild depression, heart disease, and so on. It would be no surprise if Study #1 had better outcomes. Be sure to compare yourself with those who are similar to you before applying results to your situation.
Let’s Get Technical: Understanding Statistics
Most studies have historically used the p-value to indicate whether the results of a study are significant, or clinically important. In other words, what is the chance that treatment with a new drug has no effect (the so-called null hypothesis) versus the chance that it has a positive effect? Based on tradition, a p-value of < 0.05 is used as the determination of statistical significance, or a positive result. What this means in a general sense is that a p-value of < 0.05 indicates that there is a 95% chance that the drug really works (true positive) and only a 5% chance that it does not (false positive). A p-value of < 0.01 is considered “highly significant.”
The proper use of statistics is more complicated than the above explanation. Some studies involve thousands of patients, while others involve relatively few patients. A false positive error (also called type I, or α error) using p < 0.05 means that the drug may not really work AND is greater in smaller studies. Studies with more participants are said to have a higher power. Studies must be large enough to avoid concluding that the effectiveness of a new treatment is the same as that of the standard treatment or placebo (i.e., a false negative result, also called a type II, or β error) when it is in reality better. What if the results of a study of a new versus the standard drug are deemed negative because it results in a p-value of, for example, 0.1 or 0.06? This is just above the arbitrary 0.05 level, below which studies are considered significant by convention. Is this truly a negative result? More sophisticated statistical analysis (using a technique called confidence limits or intervals), or repeated and larger studies, can sometimes help determine the “truth” about a new drug.
• Understanding Surveys
Sometimes information is conveyed by way of surveys. Surveys are not evidence-based. Survey results may be misleading and should not be used to make medical decisions. However, surveys and polls may promote a product or an opinion, so knowing how to evaluate them is important.
Who is funding the web site from which you get your information? Advertising on a web site tells you who, but even websites without ads may be paid for by commercial interests.
How a question is asked may influence the outcome. For example, Alice takes a poll that asks, “Should we invest more money into access to better healthcare?” Most people will probably favor this. Alice’s opponent Betty asks, “Should we raise taxes to fund big government by passing a healthcare funding bill?” Now people are likely to oppose this. However, both Alice and Betty will use the survey results to support their positions.
The survey sample size is a significant factor that may be misleading. For instance, if two people are asked their opinion about Brand X and they both liked it, then it looks like 100% of the people surveyed liked Brand X. However if two more people are surveyed and their opinion differs from the first two, then that number drops to 50%.
There is another way to manipulate statistics using sample size and perseverence. Brand A wants to be the best and hopes to claim that at least four out of five doctors recommend their product. They ask the opinions of five doctors. If only one endorses Brand A, they ask five more doctors. If only three of them recommend it, they keep asking until they get four out of five. The surveyor is under no obligation to tell you that they asked 100 doctors before finding the desired response.
Look for web sites that end in .gov or .org rather than .com
Watch for bias. Even well-meaning researchers are biased. Suppose a researcher wants to prove his/her belief that HCV patients who are optimists fare better during treatment than pessimists do. This may affect the outcome before the study even begins. The researcher suspects the answer before the study starts and is looking for proof to support that belief. In subtle ways, this prejudice may influence the study design, conduct, and interpretation of data. The best way to conduct a study is with no preconceived notion of the outcome.
• The Internet as a Source
The Internet is a valuable tool. However, like any tool, one needs to know how to use it well. The following are some suggestions for how to use the Internet more effectively:
• Find out if the information comes from a reliable source. Information from independent and not-for-profit sources, particularly from the U.S. federal government (e.g., National Institutes of Health (NIH), FDA), a general medical society (e.g., American Medical Association) or specialty or disease society (e.g., American Association for the Study of Liver Diseases) is likely to be reliable. Commercial sources (e.g., pharmaceutical companies) may be scientifically accurate, but may emphasize the positive aspects of a drug for marketing purposes.
• Look for information that includes author names, medical affiliations, references, and publication dates.
• Information provided in chat rooms and discussion forums is frequently anecdotal and based on individual experiences, which often cannot be generalized to all people with the same condition.
• Question what you read. Does the research stand up to careful scrutiny?
• Do not panic. It is easy to be overwhelmed and frightened by what appears to be “bad news.” Get more information before overreacting.
• Never use the Internet as a substitute for medical care.
• The Bottom Line
Most of us rely on numbers. Numbers seem black and white. After all, two plus two equals four. However, the reliability of numbers is only as good as the humans interpreting them. So, how do we know what to trust? How can we separate fact from fiction? Here are some suggestions:
1. Look at the source. If statistics are used for commercial or political purposes, the numbers may have been spun. If the numbers come from a reliable medical journal, such as Hepatology, New England Journal of Medicine, or Lancet, it is likely that these have stood up to scrutiny.
2. Compare apples to apples. If the subjects in a study were all Caucasian males over the age of 40, then the information may not apply to a 20-year-old African American female.
3. Use critical thinking. Ask questions. Assume nothing. Challenge what you read.
4. Check the source of funding for the research. It is not objective research if the data for the product comes solely from the manufacturer. Data needs to be verified independently by more than one source before it can be considered reliable.
5. Do not let emotions get in the way of facts. It is disturbing to read about HCV, but the majority of us will die with HCV and not of HCV.
6. Get a reliable second opinion to confirm your understanding of the research.
7. Seek opinions from others who respect evidence-based medicine. They may have already found the information you are seeking.
8. Keep an open mind. Do not form an opinion and look for the facts to conform to your opinion. This means you are biased too.
A Final Word
Never let research tell you how you feel. If half of surveyed HCV patients report feeling fatigued, that does not mean you should or will feel fatigue. No lab test or research should ever tell you how you feel. Data may be reassuring, but it is not a substitute for your opinion about your health. It takes years of education and experience to become an expert in the field of research. This guide provides tools to assist those who are interested in learning more about clinical research and HCV. A curious mind coupled with time and practice can open the doors to knowledge. As the saying goes, knowledge is power.
APENDIX A:
Resources
Hepatitis C Support Project:
Informed Health Online:
Medline Plus Medical Dictionary
Medline’s Understanding Medical Research
National Institutes of Health (NIH):
NIH Clinical Trials Web site:
New York Online Access to Health:
Patient Inform:
The Cochrane Collaboration
United States National Library of Medicine:
APENDIX B:
Glossary
Abstract – a brief summary of important points of a research article or other text.
Adverse event – an undesired action or effect of an experimental treatment.
Anecdotal evidence – the collection of information based on clinicians’ observations.
Antibody – a protein produced by the immune system when a foreign substance enters the body. The presence of antibodies is an indicator of a past or possibly current infection. HCV antibodies are written as anti-HCV. The test for anti-HCV is often the first step in diagnosing chronic HCV infection. A positive anti-HCV test must be followed by other laboratory tests in order to confirm the diagnosis. The antibody test alone is not sufficient to make a diagnosis of chronic HCV infection.
Biopsy – a procedure in which a sample of cells or tissue is taken to examine in a laboratory. In HCV, liver biopsies are used to monitor the health of the liver.
Blind or double-blind study – this refers to whether or not the research team or study participants know whether the participants are receiving a placebo or the experimental drug. In a blinded study, the participants do not know if they are receiving the test drug or the placebo. In a double-blind study, neither the participants nor the researchers who administer the treatment know who is receiving the experimental drug or the placebo. In the case of medical necessity, a study can be unblinded to reveal who is and is not receiving the experimental treatment.
Citation – refers to the source of the information
Combination therapy – two or more drugs that are used in combination with each other in order to improve the effectiveness of treatment. When applied to HCV treatment, this term most often refers to the use of interferon plus ribavirin.
Control group – the group of participants in a clinical trial who receive the current standard treatment or no active treatment, and not the new drug under study.
Efficacy – refers to the drug’s effectiveness, i.e., if it works.
Endpoints – The outcomes used to judge the effectiveness of the treatments.
Evidence-based medicine – Used by medical providers, this is the practice of using solid research in order to formulate treatment recommendations.
Exclusion criteria – conditions that disqualify someone from participating in a clinical trial.
Experimental group – the group of study participants who receive the new experimental treatment.
FDA – abbreviation for the Food and Drug Administration. This U.S. federal government agency has many functions. It is responsible for granting or denying approval for drugs to be sold to the public.
Genotype – genetic variation in the structure of a virus. HCV has six major genotypes, designated by the numbers 1 through 6. There are also many subtypes, e.g., 1a, 1b, 2a, etc. In the U.S., genotype 1 is predominant (approximately 70-75% of patients).
Half-life – the period of time it takes for the concentration of a drug to decrease to half its original concentration in the blood.
HCV RNA – the genetic material of the hepatitis C virus. HCV is a singlestranded ribonucleic acid (RNA) virus.
HCV polymerase inhibitor – an agent that inhibits HCV replication by interfering with the virus’ polymerase enzyme.
HCV protease inhibitor – an agent that inhibits HCV replication by interfering with the virus’ protease enzyme.
Inclusion criteria – conditions that must be met in order to be eligible for a clinical trial.
Institutional review board (IRB) – an IRB is a group that has been formally designated to review and monitor research involving human subjects. It has the authority to approve, require modifications in, or disapprove research. The purpose of IRB review is to protect the rights and welfare of humans participating in research.
Interferon-alfa – a naturally occurring protein in the human body produced by the immune system. Interferon interferes with viral replication. Genetically engineered products based on the natural protein have been developed by several pharmaceutical companies, and are approved for the treatment of chronic HCV infection.
Investigational new drug (IND) – a drug that the FDA allows to be used in human clinical trials in order to gain information for evaluation by the FDA, usually for approval for commercial marketing.
Investigator – a clinical researcher who is involved with a clinical trial protocol and its implementation. The Principal Investigator is ultimately responsible for the conduct of the trial.
Off-label – use of an FDA-approved drug for an indication other than that for which it was approved.
Open-label trial – a clinical trial in which doctors and participants know which drug is being administered.
P-value – a measure of probability that is reported with clinical trial results. The p-value indicates the likelihood the results obtained are not due to chance alone. Traditionally, a p-value of less than .05 is considered statistically significant or not likely due to chance alone.
Peer review – review of a clinical trial by experts who were not associated with the research. Looks at scientific merit, participant safety, and ethical considerations.
Pegylated interferon (PegIntron™, Pegasys®) – a form of interferon that has a long half-life in the body and be can be injected less often (typically a week). Pegylated interferon is approved for the treatment of HCV.
Placebo – a pill (capsule, liquid, or injection) that contains an inactive substance. It is compared to the experimental drug in placebocontrolled clinical trials.
Protocol – a written document that states the guidelines of how a clinical trial will be conducted. A protocol includes all of the details of the study, including who can participate, how the study drug will be administered, drug side effects, and risks.
Randomization – the process of randomly assigning study participants to either the control (standard treatment or no treatment) or experimental (new drug) group.
Ribavirin – an antiviral medication that is used in combination with an interferon product for treatment of chronic HCV infection.
Risk/benefit ratio – a measurement used to evaluate whether potential benefits outweigh potential risks.
Safety – refers to the drug’s toxicity or side effects.
Single-blinded study – this refers to a study in which the participants do not know if they are receiving the test substance or the placebo. See blind/double-blind study.
Standard of care – the level of care that all persons with a particular illness should receive; the level below which care would be considered substandard.
Standard treatment – the best or most widely used currently available treatment.
Study arm – clinical trials usually compare the responses of two or more groups of subjects (e.g., control and treatment groups). If a study has more than one treatment group (for example, receiving varying dosages of a drug), the different groups are called study arms.
Sponsor – the sponsor of new drug studies is typically a drug or biologic manufacturer. Other potential sponsors include a university or independent foundation supporting the research.
Subject – a volunteer participant in a clinical trial.
Treatment-naïve – a person who has not had prior treatment for a particular condition.
Viral load – the amount of virus (i.e., the HCV RNA level) that can be measured, usually in the blood.
Viral replication – the ability of a virus to reproduce copies of itself.
Virus – a microscopic infectious particle that invades a living organism and makes copies of itself (viral replication).
APENDIX C:
Questions To Ask About Clinical Trials
Since clinical trials vary, below are some questions to ask when considering participation:
• What is the purpose of the study?
• What is the drug or combination of drugs being tested?
• What is the study phase? If the trial is in an early phase, how many humans have received the study drug? What is known about animal studies using this drug?
• Is a placebo being used? If so, what are the chances of receiving the study drug versus the placebo? If I receive the placebo, will I be offered the study drug at the end of the trial period?
• If this is a double-blind placebo study, when can I expect to know if I received the placebo or the study drug?
• What side effects can I expect from the study drug? Are there any serious risks? If I were harmed because of the research, what treatment would I be entitled to receive?
• What are the potential benefits or risks of my participation in the study?
• What other treatment or non-drug options are open to me if I do not participate in the study?
• Will I receive lab tests or other diagnostic tests throughout the study? If so, how often? Will I be told the results during the study or will the results be revealed after the end of the trial?
• What are my responsibilities as a participant?
• How long does the study last? How many visits are required? Are appointments at specific times or is the schedule flexible? Are there any other expectations that will require my time and effort?
• Where is the study being conducted?
• What should I tell my family or coworkers regarding my participation in the trial?
• Will I continue to see my regular physician if I participate in the study?
• Will I incur any costs? Will any of the treatment or tests be free?
• How many subjects will participate in the study?
• Will I be able to continue taking my regular medications or supplements (including prescription and over-the-counter medications, vitamins, minerals, and herbs)?
Lucinda Porter, R.N., B.A. has been with the Hepatitis C Support Project (HCSP) since 1998. She has written for a variety of publications, including a regular column for the HCV Advocate. Ms. Porter was a clinical coordinator at Stanford University Medical Center’s Hepatology clinical research division. She has lived with HCV since 1988 and has participated in various clinical trials, both as a subject and as a research nurse.
Acknowledgement: Portions of this guide are excerpts from a previous HCSP publication, A Guide to Understanding Clinical Trials and Medical Research in Hepatitis, written by Emmet B. Keeffe, MD, and Lucinda K. Porter, RN. Emmet has granted permission to use material from that publication. HCSP and Lucinda extend their gratitude for his prior contributions.
Hepatitis C Support Project
Alan Franciscus
Executive Director, Hepatitis C Support Project
Founder, Editor-in-Chief, HCSP Publications
C.D. Mazoff, PhD
Webmaster, Managing Editor
© copyright 2010 • Version 1.1 June 2010
Transplant reunion a celebration
Alisa Sutton and her transplant surgeon, Dr. Byers Shaw.
Published Sunday July 18, 2010
By Rick Ruggles
WORLD-HERALD STAFF WRITER
Judy Attrill knew her daughter's liver transplant had gone well because the toddler was no longer yellow.
The girl, Alisa, wasn't yet 3 years old and had been gravely ill with liver disease since infancy. A doctor had told the family when Alisa was a baby that she wouldn't live much longer.
The Attrills learned in 1985 that Dr. Byers Shaw had been recruited from Pittsburgh to the Nebraska Medical Center to create a liver-transplant program. That summer Alisa became the first child and fourth patient to receive a liver transplant at the medical center.
“We were so excited,” said her mother, of Hinton, Iowa. “It went smooth. They told us it would be 12 hours in surgery, maybe, and it was five. ... Right away her coloring was different. She was pinking up.”
The now-married Alisa Sutton attended the Nebraska Medical Center's transplant reunion Saturday at the Holiday Inn convention center. Surgeons at the medical center have performed 2,600 liver transplants in 25 years. Surgeons have transplanted 3,000 other organs including hearts, kidneys, pancreases and small bowels.
A thousand transplant recipients, family members and staffers attended the reunion, which is a celebration of the program and its survivors.
Shaw said he's ill at ease at transplant reunions, but he came Saturday. He dislikes when the word “miracle” is associated with transplants. “You're trained to do these things,” Shaw said the day before the reunion.
There's another reason for his discomfort. “All of us have had plenty of failures,” said Shaw, 60. “I can't help but be reminded of those failures.”
Shaw was heavily recruited in the mid-1980s by hospitals that wanted to build liver-transplant programs. He liked the Nebraska Medical Center in part because its leaders and staff understood it would take additional training. Leaders at some institutions were arrogant, he said, and suggested they were already prepared to do liver transplants.
At the medical center, anesthesiologists willingly went to Pittsburgh for training, and Dr. Rod Markin, now interim dean of medicine at the University of Nebraska Medical Center, went to Pittsburgh and Minnesota to gain expertise in examining liver biopsies after transplants.
Shaw stopped doing liver transplants about seven years ago. He said the late-night phone calls summoning him for surgery became “a source of incredible dread” and even terror.
“You grit your teeth and just go ahead,” he said. He'd be ready for work once he got in his car, he said, but it's a relief to no longer take those calls.
To Sutton, 27, now of Sioux City, Iowa, Shaw is the man whose expertise gave her new life. “I can't believe it,” she said after her mother told the story of her battle to survive 25 years ago. “It's amazing I'm still alive.”
Sutton attended the transplant reunion with her family, including her parents, her husband, their baby boy and their two little blonde girls. One girl sat on Mom's lap, the other on Grandma's. That's a scene Grandma Attrill once wouldn't have thought possible. It is, she said, unbelievable.
Contact the writer:
444-1123, rick.ruggles@owh.com
Source
July 17, 2010
Can Human Liver Stem Cells repair or replace liver function deficiency associated with cancer, hepatitis, or genetic diseases?
Over 26,000 people die each year in the United States from chronic liver disease. One in ten Americans suffers from liver disease, and for many of them there are no effective treatments. The goal of our Liver Stem Cell Program is to repair damaged or diseased livers.
What have we accomplished so far?
Our work on liver stem and progenitor cells began in collaboration with Markus Grompe, Ph.D., of Oregon Health Science University. Dr. Grompe's work focuses on the discovery and development of methods for identifying and assessing the therapeutic potential of liver stem and progenitor cells. We obtained rights to a mouse model of liver failure developed by Dr.Grompe, the “FAH knockout mouse,” which lacks a key enzyme, FAH, or fumaryl-acetoacetate hydrolase. This mouse was developed to mimic a fatal human genetically-based liver disease called tyrosinemia type I. Toxic substances build up in these mice and cause liver damage. This model has allowed us to test methods for using cell transplantation to regenerate diseased livers.
We believe that a key accomplishment of the Liver Program was to develop proprietary monoclonal antibodies that enrich for distinct subsets of human liver cells. Using these antibodies we have identified a human liver stem-like cell which we call a human liver engrafting cell (hLEC). These cells produce human serum albumin in mouse serum following transplantation into immunodeficient mice, demonstrating that the hLEC, once transplanted, is a functional cell. We have filed a patent application on the hLEC and its uses in cell therapy for liver disease.
The program will focus on demonstrating the robust engraftment and function of these hLECs in animal models of liver degeneration (such as the FAH knockout mouse) as the next step in determining whether transplanted hLECs can be used to treat liver disease.
StemCells has also devised a culture assay that it uses to identify liver stem and progenitor cells. The culture supports the proliferation of hLECs and StemCells has shown that hLECs give rise to early bipotent progenitor cells that can produce two different types of liver cells, bile duct cells and hepatocytes.
It is also possible to infect this culture with human hepatitis virus to study the virus's effects on liver cells. The culture system could be used to test drugs that act on, or are metabolized by, human liver cells.
It is our belief that a source of well-defined human cells capable of engraftment and substantial liver regeneration will provide a cell-based therapeutic product available to many more patients than liver transplants. An in vitro culture system that can reproducibly grow human liver progenitor cells may also provide cells that can be modified genetically to correct inborn errors of metabolism.
What does the future hold?
StemCells' scientists have identified other monoclonal antibodies that divide the hLEC population into additional subsets of cells which can be tested for liver stem cell activity. We have also been developing additional models for examining the engraftment of the hLECs. Furthermore, in collaboration with scientists at Stanford University, we will test whether engrafted human liver cells can be infected by human hepatitis C virus. Engrafted humanized livers may provide a test system for the development of therapies or vaccines for hepatitis C infection.
Summary of Progress
We have identified a candidate human liver stem cell-like population referred to as a human liver engrafting cell (hLEC).
We have developed an in vitro culture assay for growing the hLECs and have demonstrated that hLECS give rise to progenitor cells that express markers for both bile duct cells and hepatocytes.
We have shown that the in vitro culture of hLECs also can permit infection of a human hepatitis virus, thereby having the potential to be an assay system to screen novel anti-viral compounds.
We have demonstrated the engraftment and survival (>6 months) of the candidate human LEC in an in vivo mouse model.
We have detected human albumin in mouse serum in animals transplanted with hLECs for 6 months.
We have established a culture system for expansion of sorted hLECs.
Source
What have we accomplished so far?
Our work on liver stem and progenitor cells began in collaboration with Markus Grompe, Ph.D., of Oregon Health Science University. Dr. Grompe's work focuses on the discovery and development of methods for identifying and assessing the therapeutic potential of liver stem and progenitor cells. We obtained rights to a mouse model of liver failure developed by Dr.Grompe, the “FAH knockout mouse,” which lacks a key enzyme, FAH, or fumaryl-acetoacetate hydrolase. This mouse was developed to mimic a fatal human genetically-based liver disease called tyrosinemia type I. Toxic substances build up in these mice and cause liver damage. This model has allowed us to test methods for using cell transplantation to regenerate diseased livers.
We believe that a key accomplishment of the Liver Program was to develop proprietary monoclonal antibodies that enrich for distinct subsets of human liver cells. Using these antibodies we have identified a human liver stem-like cell which we call a human liver engrafting cell (hLEC). These cells produce human serum albumin in mouse serum following transplantation into immunodeficient mice, demonstrating that the hLEC, once transplanted, is a functional cell. We have filed a patent application on the hLEC and its uses in cell therapy for liver disease.
The program will focus on demonstrating the robust engraftment and function of these hLECs in animal models of liver degeneration (such as the FAH knockout mouse) as the next step in determining whether transplanted hLECs can be used to treat liver disease.
StemCells has also devised a culture assay that it uses to identify liver stem and progenitor cells. The culture supports the proliferation of hLECs and StemCells has shown that hLECs give rise to early bipotent progenitor cells that can produce two different types of liver cells, bile duct cells and hepatocytes.
It is also possible to infect this culture with human hepatitis virus to study the virus's effects on liver cells. The culture system could be used to test drugs that act on, or are metabolized by, human liver cells.
It is our belief that a source of well-defined human cells capable of engraftment and substantial liver regeneration will provide a cell-based therapeutic product available to many more patients than liver transplants. An in vitro culture system that can reproducibly grow human liver progenitor cells may also provide cells that can be modified genetically to correct inborn errors of metabolism.
What does the future hold?
StemCells' scientists have identified other monoclonal antibodies that divide the hLEC population into additional subsets of cells which can be tested for liver stem cell activity. We have also been developing additional models for examining the engraftment of the hLECs. Furthermore, in collaboration with scientists at Stanford University, we will test whether engrafted human liver cells can be infected by human hepatitis C virus. Engrafted humanized livers may provide a test system for the development of therapies or vaccines for hepatitis C infection.
Summary of Progress
We have identified a candidate human liver stem cell-like population referred to as a human liver engrafting cell (hLEC).
We have developed an in vitro culture assay for growing the hLECs and have demonstrated that hLECS give rise to progenitor cells that express markers for both bile duct cells and hepatocytes.
We have shown that the in vitro culture of hLECs also can permit infection of a human hepatitis virus, thereby having the potential to be an assay system to screen novel anti-viral compounds.
We have demonstrated the engraftment and survival (>6 months) of the candidate human LEC in an in vivo mouse model.
We have detected human albumin in mouse serum in animals transplanted with hLECs for 6 months.
We have established a culture system for expansion of sorted hLECs.
Source
Medical marijuana users in New Mexico Jonesing for bigger supply
July 17, 6:37 PM Albuquerque Science Examiner Aaron Cowan
Supplies of “medical marijuana” are reported running low for the approximately 2000 patients who are currently approved to receive it as a treatment, according to at least one supplier in Albuquerque, New Mexico, as of July 17, 2010. In addition, it is estimated that about 200 new patients are approved to receive the drug every month. Patients can also apply for permits to grow it themselves, but apparently, the majority of patients rely upon suppliers instead. Fortunately, six new suppliers have been licensed in the state, but suppliers are limited in the number of plants they can have, and one supplier says that he has five times the patients that he is able to supply.
New Mexico has some fairly limited guidelines for medical marijuana use, first enacted in 2007, for use under a physicians direction. A patient must have cancer, glaucoma, multiple sclerosis, epilepsy, spinal cord damage, HIV/AIDS, or be in hospice to qualify. Conditions still pending approval by the Department of Health are Hepatitis C, post-traumatic stress disorder, and nerve pain. Suppliers can grow up to 95 plants at one time.
In terms of the scientific research, that’s where things get tricky. According to this article in Scientific American, the current federal restrictions which are still in place on marijuana research are hampering efforts to study it. However, there are some fairly serious organizations such as the MAPS organization, which has been working for over a decade to study the effectiveness of marijuana as a medicinal compound. Conditions like cancer, glaucoma, and HIV/AIDS do seem responsive to this type of treatment, acting as an anti-emetic, in the case of AIDS or chemotherapy treatments, for example, according to some in the medical community. Of course, there is far from universal agreement that the science supports the use of medical marijuana, so readers may wish to check out the pros and cons for oneself at this link.
Source
Supplies of “medical marijuana” are reported running low for the approximately 2000 patients who are currently approved to receive it as a treatment, according to at least one supplier in Albuquerque, New Mexico, as of July 17, 2010. In addition, it is estimated that about 200 new patients are approved to receive the drug every month. Patients can also apply for permits to grow it themselves, but apparently, the majority of patients rely upon suppliers instead. Fortunately, six new suppliers have been licensed in the state, but suppliers are limited in the number of plants they can have, and one supplier says that he has five times the patients that he is able to supply.
New Mexico has some fairly limited guidelines for medical marijuana use, first enacted in 2007, for use under a physicians direction. A patient must have cancer, glaucoma, multiple sclerosis, epilepsy, spinal cord damage, HIV/AIDS, or be in hospice to qualify. Conditions still pending approval by the Department of Health are Hepatitis C, post-traumatic stress disorder, and nerve pain. Suppliers can grow up to 95 plants at one time.
In terms of the scientific research, that’s where things get tricky. According to this article in Scientific American, the current federal restrictions which are still in place on marijuana research are hampering efforts to study it. However, there are some fairly serious organizations such as the MAPS organization, which has been working for over a decade to study the effectiveness of marijuana as a medicinal compound. Conditions like cancer, glaucoma, and HIV/AIDS do seem responsive to this type of treatment, acting as an anti-emetic, in the case of AIDS or chemotherapy treatments, for example, according to some in the medical community. Of course, there is far from universal agreement that the science supports the use of medical marijuana, so readers may wish to check out the pros and cons for oneself at this link.
Source
Relapse of hepatitis C in a pegylated-interferon-α-2b plus ribavirin-treated sustained virological responder
This is the first documented case of late relapse I have seen.
Hepatology Research
Volume 40 Issue 6, Pages 654 - 660
Published Online: 25 May 2010
© 2010 The Japan Society of Hepatology
Case Report
Hideki Fujii, 1 Yoshito Itoh, 2 Naoki Ohnishi, 1 Masafumi Sakamoto, 1 Tohru Ohkawara, 1 Yoshihiko Sawa, 1 Koichi Nishida, 1 Takeshi Nishimura, 2 Kanji Yamaguchi, 2 Kohichiroh Yasui, 2 Masahito Minami, 2 Takeshi Okanoue, 3 Yasuo Ohkawara 1 and Toshikazu Yoshikawa 2
1 Department of Internal Medicine, Aiseikai Yamashina Hospital, 2 Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, and 3 Division of Gastroenterology, Saiseikai Suita Hospital, Osaka, Japan
Correspondence to Dr Yoshito Itoh, Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto 602-8566, Japan. Email: yitoh@koto.kpu-m.ac.jp
KEYWORDS
chronic hepatitis C • genotype 2a • sustained virological response • relapse • phylogenetic analyses
ABSTRACT
A 41-year-old woman with chronic hepatitis C was treated with pegylated-interferon (PEG-IFN)-α-2b plus ribavirin for 24 weeks. She had hepatitis C virus (HCV) genotype 2a (1600 KIU/mL), and her liver histology showed mild inflammation and fibrosis. Four weeks after the start of the therapy, she achieved a rapid virological response (RVR) and then a sustained virological response (SVR). Serum alanine aminotransferase (ALT) levels remained within normal ranges and HCV RNA continued to be negative. However, ALT levels flared with the re-emergence of HCV RNA in the serum 1.5 years after discontinuation of therapy. HCV RNA obtained from sera before therapy and after relapse shared a 98.6% homology with the E2 region, and phylogenetic analyses indicated that they were the same HCV strain. These results eliminated the possibility of a re-infection and strongly indicated a late relapse of the disease. Therefore, follow-up is necessary for chronic hepatitis C patients after SVR, even if they respond well to therapy, including RVR.
Received 15 September 2009; revision 23 November 2009; accepted 6 December 2009.
DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1872-034X.2010.00641.x About DOI
Source
The yellow symptom
Sunday July 18, 2010
By Dr TAN HUCK JOO
Jaundice is not a disease, but it’s a warning sign not to be dismissed.
JAUNDICE in newborns is usually harmless and lasts only for a short time, but when you see an adult with yellow skin, it implies a serious health problem that requires urgent medical attention.
A sign, not a disease
Jaundice is a sign of many diseases. There is a yellow discolouration of the skin and sclera (the whites of the eyes) due to excess bilirubin circulating in the body. This is normally accompanied by very dark urine, pale stools (if patients have bile duct obstruction), and other symptoms, such as itchy skin and occasional nausea and loss of appetite.
Why is there excess bilirubin? Bilirubin is actually a natural “waste product” arising from the normal breakdown of old red blood cells (RBC) in your body. Under normal circumstances, bilirubin undergoes certain processes in the liver before it is excreted. Bilirubin metabolites are formed in the gut and passed out in the urine and faeces. Bilirubin is also the pigment that gives your urine and faeces colour.
Many reasons can contribute to excess bilirubin in the blood. It is mostly due to problems in the liver or obstruction in the bile ducts, both of which can lead to jaundice. In rare cases, excessive bilirubin is due to haemolytic anaemia, a disorder where an abnormally large number of red blood cells are broken down.
Common causes and symptoms of jaundice
In general, jaundice can be categorised into two types: obstructive jaundice and hepatocellular jaundice.
Obstructive jaundice
Obstructive jaundice, or cholestatic jaundice, is caused by blockage in the bile ducts due to gallstones, pancreatic cancer, or bile duct cancer (cholangiocarcinoma).
Individuals with obstructive jaundice typically have dark-coloured urine and pale stools because of the reduced flow of bile and bilirubin into the intestines. Pain and fever can be felt if gallstones are present. Because the pain is located at the upper part of the abdomen, patients often misconstrue it as gastric pain.
However, patients with obstructive jaundice due to gallstones usually have upper abdominal pain which radiates to the back. On the other hand, bile duct cancer is usually painless, but can cause weight loss over time.
Obstructive jaundice caused by pancreatic cancer usually presents with pain and weight loss. It is important to pick up pancreatic cancer early and physicians should think about pancreatic cancer, especially when patients present with “gastric pain”.
Hepatocellular jaundice
Hepatocellular jaundice is caused by an injury or inflammation of the liver cells. This could be due to:
● Medications (drug-induced jaundice) – Certain prescribed medications or traditional herbal supplements may interfere with liver function. This prevents bilirubin from being efficiently removed from the blood or excreted into the bile, thus leading to jaundice.
Alcohol hepatitis is another important cause of hepatocellular jaundice.
● Viral hepatitis – Hepatitis is a condition where the liver becomes inflamed and its ability to process and secrete bilirubin is largely discounted. Common forms of viral hepatitis include viral hepatitis A, B, and C. Viral hepatitis A is normally contracted through shell fish whereas viral hepatitis B and C are through blood products and body fluids.
● Chronic liver diseases – In chronic liver diseases (e.g. chronic hepatitis B, alcoholic liver disease), scar tissue can form in the liver. Scar tissue cannot do what healthy liver tissue does. As more scar tissue replaces the normal functioning liver tissue, the liver function deteriorates (e.g. unable to clean blood, digest food, and store energy).
Ultimately, there will be jaundice. By the time jaundice is noticeable, the condition may have already become serious, and patients may experience liver failure and complications of liver cirrhosis (hardening of liver).
Finding out what’s wrong
It is important for the doctor to determine the underlying health conditions leading to the jaundice so that appropriate treatment can be given to the patient. The jaundice usually resolves once the underlying cause is treated.
History and physical examination can suggest possible reasons for the jaundice. For instance, jaundice is most likely caused by alcoholic liver disease if the patient is a heavy drinker, or may be drug-induced if patient is taking new medications recently.
Presence of abdominal pain and fever may suggest blockage of the bile duct, usually by gallstones. If there is weight loss, it could be cancer related.
Liver function tests for measuring bilirubin and liver enzymes are helpful to determine if the jaundice is due to abnormal RBC destruction, inflammation of the liver, or obstruction or disease in the bile duct. A liver function test can help suggest what is the probable cause of jaundice. Blood tests can be done to test for hepatitis A, B, and C.
An ultrasound scan of the abdomen may help to detect obstructions in bile ducts, e.g. gallstones or pancreatic cancer.
Computerised tomography (CT) scans and MRI scans are especially useful to identify tumours in the pancreas and liver. It is also useful to detect bile duct tumour.
Endoscopic ultrasound is particularly useful to examine the pancreas for tumours or small gallstones in the gallbladder and bile ducts that cannot be detected by other methods. It is also useful to take some tissues using fine needle aspiration.
Treatment for jaundice
Before a doctor treats a jaundiced patient, he has to find out the cause first, so that treatment may be directed at the specific cause. For example, hepatitis B is treated with anti-viral drugs, while a procedure called Endoscopic Retrograde Cholangiopancreatography (ERCP) is performed to remove a gallstone in the bile duct or to insert a stent in the bile duct to unblock the blockage in the bile duct due to tumour.
If the jaundice is associated with alcoholic hepatitis, the patient has to stop alcohol intake.
The main treatment for bile duct cancer is surgery to remove the tumour, but operation is not always possible. When that’s the case, a small tube (stent) will be put into the bile duct to allow the bile to flow again and relieve the jaundice.
Prevention
Jaundice can be prevented if your liver is healthy and functioning efficiently. While causes such as pancreatic cancer and bile duct cancer cannot be prevented, there are things you can do to protect your liver.
● Avoid excessive intake of alcohol.
● If you have not had hepatitis A or B, get vaccinated.
● There is no vaccine available for hepatitis C, but you can reduce your risk by practising safe sex and avoiding injecting drugs or sharing intravenous drug needles. All the needles in hospitals nowadays are single-use.
● Make sure shellfish are cooked properly before eating to prevent hepatitis A.
● For people with gallstones, eating a low-fat diet helps to reduce the attack of pain. If the gallstones give you symptoms, remove it.
As with most diseases, timely and appropriate treatment saves lives, so seek medical help as soon as you notice any signs of jaundice, or experience intense abdominal pain and fever.
Dr Tan Huck Joo is the president of the Malaysian Society of Gastroenterology & Hepatology. The author is not associated with and does not endorse any brand or product. This article is courtesy of the Malaysian Society of Gastroenterology & Hepatology and supported by the VITAGEN Healthy Tummies Programme. For a free digestive health booklet or more information, please contact 03-5621 1408.
Source
By Dr TAN HUCK JOO
Jaundice is not a disease, but it’s a warning sign not to be dismissed.
JAUNDICE in newborns is usually harmless and lasts only for a short time, but when you see an adult with yellow skin, it implies a serious health problem that requires urgent medical attention.
A sign, not a disease
Jaundice is a sign of many diseases. There is a yellow discolouration of the skin and sclera (the whites of the eyes) due to excess bilirubin circulating in the body. This is normally accompanied by very dark urine, pale stools (if patients have bile duct obstruction), and other symptoms, such as itchy skin and occasional nausea and loss of appetite.
Why is there excess bilirubin? Bilirubin is actually a natural “waste product” arising from the normal breakdown of old red blood cells (RBC) in your body. Under normal circumstances, bilirubin undergoes certain processes in the liver before it is excreted. Bilirubin metabolites are formed in the gut and passed out in the urine and faeces. Bilirubin is also the pigment that gives your urine and faeces colour.
Many reasons can contribute to excess bilirubin in the blood. It is mostly due to problems in the liver or obstruction in the bile ducts, both of which can lead to jaundice. In rare cases, excessive bilirubin is due to haemolytic anaemia, a disorder where an abnormally large number of red blood cells are broken down.
Common causes and symptoms of jaundice
In general, jaundice can be categorised into two types: obstructive jaundice and hepatocellular jaundice.
Obstructive jaundice
Obstructive jaundice, or cholestatic jaundice, is caused by blockage in the bile ducts due to gallstones, pancreatic cancer, or bile duct cancer (cholangiocarcinoma).
Individuals with obstructive jaundice typically have dark-coloured urine and pale stools because of the reduced flow of bile and bilirubin into the intestines. Pain and fever can be felt if gallstones are present. Because the pain is located at the upper part of the abdomen, patients often misconstrue it as gastric pain.
However, patients with obstructive jaundice due to gallstones usually have upper abdominal pain which radiates to the back. On the other hand, bile duct cancer is usually painless, but can cause weight loss over time.
Obstructive jaundice caused by pancreatic cancer usually presents with pain and weight loss. It is important to pick up pancreatic cancer early and physicians should think about pancreatic cancer, especially when patients present with “gastric pain”.
Hepatocellular jaundice
Hepatocellular jaundice is caused by an injury or inflammation of the liver cells. This could be due to:
● Medications (drug-induced jaundice) – Certain prescribed medications or traditional herbal supplements may interfere with liver function. This prevents bilirubin from being efficiently removed from the blood or excreted into the bile, thus leading to jaundice.
Alcohol hepatitis is another important cause of hepatocellular jaundice.
● Viral hepatitis – Hepatitis is a condition where the liver becomes inflamed and its ability to process and secrete bilirubin is largely discounted. Common forms of viral hepatitis include viral hepatitis A, B, and C. Viral hepatitis A is normally contracted through shell fish whereas viral hepatitis B and C are through blood products and body fluids.
● Chronic liver diseases – In chronic liver diseases (e.g. chronic hepatitis B, alcoholic liver disease), scar tissue can form in the liver. Scar tissue cannot do what healthy liver tissue does. As more scar tissue replaces the normal functioning liver tissue, the liver function deteriorates (e.g. unable to clean blood, digest food, and store energy).
Ultimately, there will be jaundice. By the time jaundice is noticeable, the condition may have already become serious, and patients may experience liver failure and complications of liver cirrhosis (hardening of liver).
Finding out what’s wrong
It is important for the doctor to determine the underlying health conditions leading to the jaundice so that appropriate treatment can be given to the patient. The jaundice usually resolves once the underlying cause is treated.
History and physical examination can suggest possible reasons for the jaundice. For instance, jaundice is most likely caused by alcoholic liver disease if the patient is a heavy drinker, or may be drug-induced if patient is taking new medications recently.
Presence of abdominal pain and fever may suggest blockage of the bile duct, usually by gallstones. If there is weight loss, it could be cancer related.
Liver function tests for measuring bilirubin and liver enzymes are helpful to determine if the jaundice is due to abnormal RBC destruction, inflammation of the liver, or obstruction or disease in the bile duct. A liver function test can help suggest what is the probable cause of jaundice. Blood tests can be done to test for hepatitis A, B, and C.
An ultrasound scan of the abdomen may help to detect obstructions in bile ducts, e.g. gallstones or pancreatic cancer.
Computerised tomography (CT) scans and MRI scans are especially useful to identify tumours in the pancreas and liver. It is also useful to detect bile duct tumour.
Endoscopic ultrasound is particularly useful to examine the pancreas for tumours or small gallstones in the gallbladder and bile ducts that cannot be detected by other methods. It is also useful to take some tissues using fine needle aspiration.
Treatment for jaundice
Before a doctor treats a jaundiced patient, he has to find out the cause first, so that treatment may be directed at the specific cause. For example, hepatitis B is treated with anti-viral drugs, while a procedure called Endoscopic Retrograde Cholangiopancreatography (ERCP) is performed to remove a gallstone in the bile duct or to insert a stent in the bile duct to unblock the blockage in the bile duct due to tumour.
If the jaundice is associated with alcoholic hepatitis, the patient has to stop alcohol intake.
The main treatment for bile duct cancer is surgery to remove the tumour, but operation is not always possible. When that’s the case, a small tube (stent) will be put into the bile duct to allow the bile to flow again and relieve the jaundice.
Prevention
Jaundice can be prevented if your liver is healthy and functioning efficiently. While causes such as pancreatic cancer and bile duct cancer cannot be prevented, there are things you can do to protect your liver.
● Avoid excessive intake of alcohol.
● If you have not had hepatitis A or B, get vaccinated.
● There is no vaccine available for hepatitis C, but you can reduce your risk by practising safe sex and avoiding injecting drugs or sharing intravenous drug needles. All the needles in hospitals nowadays are single-use.
● Make sure shellfish are cooked properly before eating to prevent hepatitis A.
● For people with gallstones, eating a low-fat diet helps to reduce the attack of pain. If the gallstones give you symptoms, remove it.
As with most diseases, timely and appropriate treatment saves lives, so seek medical help as soon as you notice any signs of jaundice, or experience intense abdominal pain and fever.
Dr Tan Huck Joo is the president of the Malaysian Society of Gastroenterology & Hepatology. The author is not associated with and does not endorse any brand or product. This article is courtesy of the Malaysian Society of Gastroenterology & Hepatology and supported by the VITAGEN Healthy Tummies Programme. For a free digestive health booklet or more information, please contact 03-5621 1408.
Source
Impact of Peginterferon Maintenance Therapy on the Risk of Developing Hepatocellular Carcinoma in Patients with Chronic Hepatitis C Virus
Mitchell L. Shiffman
Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, Va., USA
Address of Corresponding Author
Oncology 2010;78 (Suppl. 1):11-16 (DOI: 10.1159/000315224)
Key Words
Hepatocellular carcinoma
Hepatitis C virus
Peginterferon
Sustained virologic response
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing worldwide. This is largely to do with the epidemic of chronic hepatitis C virus (HCV) in the USA and other developed countries and an increasing prevalence of cirrhosis. The current treatment for chronic HCV is peginterferon (Peg-IFN) and ribavirin. Unfortunately, response rates are limited especially in patients with cirrhosis. Several observations have led to the hypothesis that continuing Peg-IFN as maintenance therapy in patients with chronic HCV and cirrhosis could reduce the risk of developing complications including HCC. However, three large prospective controlled trials of maintenance therapy have now failed to demonstrate that Peg-IFN maintenance therapy reduces complications of cirrhosis, HCC and liver-related mortality. In the HALT-C trial, the only one of these three studies for which HCV RNA data is available during maintenance therapy, only a minimal reduction in serum HCV RNA level was observed during maintenance therapy. It therefore remains uncertain if profound and persistent virologic suppression to undetectable levels of HCV RNA impacts the risk of developing HCC in patients with chronic HCV and advanced fibrosis or cirrhosis. Based upon the available data, there appears to be no rationale for utilizing Peg-IFN maintenance therapy in patients with cirrhosis and this approach does not reduce the risk of HCC.
Copyright © 2010 S. Karger AG, Basel
Author Contacts
Mitchell L. Shiffman, MD
Hepatology Section, Virginia Commonwealth University Medical Center
Box 980341, Richmond, VA 23298 (USA)
Tel. +1 804 828 4060, Fax +1 804 828 4945
E-Mail mshiffma@vcu.edu
Article Information
Published online: July 8, 2010
Number of Print Pages : 6
Source
Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, Va., USA
Address of Corresponding Author
Oncology 2010;78 (Suppl. 1):11-16 (DOI: 10.1159/000315224)
Key Words
Hepatocellular carcinoma
Hepatitis C virus
Peginterferon
Sustained virologic response
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing worldwide. This is largely to do with the epidemic of chronic hepatitis C virus (HCV) in the USA and other developed countries and an increasing prevalence of cirrhosis. The current treatment for chronic HCV is peginterferon (Peg-IFN) and ribavirin. Unfortunately, response rates are limited especially in patients with cirrhosis. Several observations have led to the hypothesis that continuing Peg-IFN as maintenance therapy in patients with chronic HCV and cirrhosis could reduce the risk of developing complications including HCC. However, three large prospective controlled trials of maintenance therapy have now failed to demonstrate that Peg-IFN maintenance therapy reduces complications of cirrhosis, HCC and liver-related mortality. In the HALT-C trial, the only one of these three studies for which HCV RNA data is available during maintenance therapy, only a minimal reduction in serum HCV RNA level was observed during maintenance therapy. It therefore remains uncertain if profound and persistent virologic suppression to undetectable levels of HCV RNA impacts the risk of developing HCC in patients with chronic HCV and advanced fibrosis or cirrhosis. Based upon the available data, there appears to be no rationale for utilizing Peg-IFN maintenance therapy in patients with cirrhosis and this approach does not reduce the risk of HCC.
Copyright © 2010 S. Karger AG, Basel
Author Contacts
Mitchell L. Shiffman, MD
Hepatology Section, Virginia Commonwealth University Medical Center
Box 980341, Richmond, VA 23298 (USA)
Tel. +1 804 828 4060, Fax +1 804 828 4945
E-Mail mshiffma@vcu.edu
Article Information
Published online: July 8, 2010
Number of Print Pages : 6
Source
Is sexual contact a major mode of hepatitis C virus transmission?
Hepatology
Early View (Articles online in advance of print)
Published Online: 16 Jun 2010
Copyright © 2010 American Association for the Study of Liver Diseases
Rania A. Tohme 1 2 *, Scott D. Holmberg 1
1 Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Atlanta, GA
2 Epidemic Intelligence Service, Office of Workforce and Career Development, Centers for Disease Control and Prevention, Atlanta, GA
email: Rania A. Tohme (rtohme@cdc.gov)
*Correspondence to Rania A. Tohme, 1600 Clifton Road NE, Centers for Disease Control and Prevention Mailstop G-37, Atlanta, GA 30333
Potential conflict of interest: Nothing to report.
fax: 404-718-8585
Abstract
Medical opinion varies considerably regarding the transmission of hepatitis C virus (HCV) through sexual contact. Based on the study design, representativeness of the study population, and the methods used for case ascertainment, we analyzed 80 qualifying reports regarding the evidence for or against sexual transmission. Regarding heterosexual transmission, the weight of evidence is that there is no increased risk of sexual transmission of HCV among heterosexual couples in regular relationships. This risk increases among persons with multiple sexual partners (adjusted odds ratio [aOR] 2.2-2.9), but this association may be confounded by increased likelihood of injection drug use with increased number of partners. There appears to be a real increased risk for women coinfected with human immunodeficiency virus (HIV) or other sexually transmitted infections (aOR 3.3-3.9) and especially for HIV-infected gay men who are having sex with one another compared with HIV-uninfected men (aOR 4.1-5.7). HIV-infected gay men increase their risk of such transmission in association with practices that lead to mucosal trauma (multiple sexual partners, fisting, use of sex toys) and the presence of genital ulcerative disease. Conclusion: This review should inform, and not distract from, recommendations to reduce the risk of HCV transmission. Health care providers need to pay special attention to sexual transmission of HCV among HIV-infected individuals. HEPATOLOGY 2010
Received: 4 March 2010; Accepted: 8 June 2010
Digital Object Identifier (DOI)
10.1002/hep.23808 About DOI
Source
Early View (Articles online in advance of print)
Published Online: 16 Jun 2010
Copyright © 2010 American Association for the Study of Liver Diseases
Rania A. Tohme 1 2 *, Scott D. Holmberg 1
1 Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Atlanta, GA
2 Epidemic Intelligence Service, Office of Workforce and Career Development, Centers for Disease Control and Prevention, Atlanta, GA
email: Rania A. Tohme (rtohme@cdc.gov)
*Correspondence to Rania A. Tohme, 1600 Clifton Road NE, Centers for Disease Control and Prevention Mailstop G-37, Atlanta, GA 30333
Potential conflict of interest: Nothing to report.
fax: 404-718-8585
Abstract
Medical opinion varies considerably regarding the transmission of hepatitis C virus (HCV) through sexual contact. Based on the study design, representativeness of the study population, and the methods used for case ascertainment, we analyzed 80 qualifying reports regarding the evidence for or against sexual transmission. Regarding heterosexual transmission, the weight of evidence is that there is no increased risk of sexual transmission of HCV among heterosexual couples in regular relationships. This risk increases among persons with multiple sexual partners (adjusted odds ratio [aOR] 2.2-2.9), but this association may be confounded by increased likelihood of injection drug use with increased number of partners. There appears to be a real increased risk for women coinfected with human immunodeficiency virus (HIV) or other sexually transmitted infections (aOR 3.3-3.9) and especially for HIV-infected gay men who are having sex with one another compared with HIV-uninfected men (aOR 4.1-5.7). HIV-infected gay men increase their risk of such transmission in association with practices that lead to mucosal trauma (multiple sexual partners, fisting, use of sex toys) and the presence of genital ulcerative disease. Conclusion: This review should inform, and not distract from, recommendations to reduce the risk of HCV transmission. Health care providers need to pay special attention to sexual transmission of HCV among HIV-infected individuals. HEPATOLOGY 2010
Received: 4 March 2010; Accepted: 8 June 2010
Digital Object Identifier (DOI)
10.1002/hep.23808 About DOI
Source
Couple recalls Steinbrenner's penchant for giving
Becky Wells holds a letter she received from late New York Yankees owner George Steinbrenner after the baseball mogul provided assistance to help Wells overcome a bout of Hepatitis C in 1992. Steinbrenner, a Cleveland-area native who devoted much time and many resources to causes in his home state, died Tuesday at 80. (Abigail S. Fisher, Eagle-Gazette)
Late Yankees owner, a native Ohioan, helped with transplant that prolonged Lancaster woman's life
BY JOE ARNOLD • The Eagle-Gazette Staff • July 17, 2010
LANCASTER -- Tom and Becky Wells knew the real George Steinbrenner. The caricature splashed across the back pages of New York's tabloids for almost 40 years wasn't the man the Lancaster couple had come to know.
Sure Steinbrenner had power. And money? More than he could shake a bat at. But the late owner of the New York Yankees, who died Tuesday, knew how to wield both for good. As he went about fiercely transforming the Yankees from a laughingstock to a billion dollar empire, Steinbrenner quietly worked for his fellow man.
In 1992, Becky Wells was sicker than she'd ever been. Diagnosed with Hepatitis C following a blood transfusion, the disease led to cirrhosis of the liver and eventually early stage liver failure. Biweekly blood transfusions kept Becky alive for six months until her first liver was found.
"I didn't have very long to live when I had the transplant," she said. "It was life or death. I was one of the lucky ones."
GOOD FRIENDS
Work forced Tom and Becky Wells to move from Lancaster to Tampa, Fla., in 1984. Tom was a salesman for Levy Awards & Promotional Products when he caught the eye of owner George A. Levy. By the time Becky fell ill, Levy, a well-known trophy and award manufacturer, had become a close friend of the couple.
Levy had introduced Tom to the Tampa Sports Club, and before long, Wells was president of the philanthropic group. Among the organization's most visible -- and generous -- members was Steinbrenner, a Cleveland native.
"He could be tough. He was a tough guy," Tom said. "But he was also good to a lot of people."
As word of Becky's illness spread within the Wells' circle of friends, it put into motion a series of events the couple believes started with Levy and Steinbrenner.
Steinbrenner, Becky said, was a well-known supporter of the Cleveland Clinic and the medical miracles the hospital performed almost daily. When Steinbrenner got wind of Becky's illness -- through Levy --he helped Becky obtain a liver after just six months on the organ waiting list, Becky said.
"Mr. Steinbrenner made some calls," she said. "He was on the board at the Cleveland Clinic, and the next think I knew, I had my liver."
AIR STEINBRENNER
The transplant, however, wasn't without complications. Becky actually was awarded two livers in 1992. After flying privately from Tampa to Cleveland, Becky and Tom got word that the liver earmarked for Becky was in Michigan, and a snowstorm had prevented the pilot in charge of picking up the organ from landing.
Four days later, the couple was told on a Sunday that another liver was available. Strapped for cash because of the flight earlier in the week, they wondered how they would arrange another short-notice flight.
"That time we were out of money, and our insurance wasn't going to cover it right away," Becky said. "Mr. Levy and Mr. Steinbrenner were instrumental in getting our transportation going."
Becky and Tom arrived in Cleveland in time for the transplant that has kept her alive since.
'HE WAS A GOOD MAN'
Save for occasional blood work and checkups, Becky hasn't had any problems with her new liver. She sent Steinbrenner a thank-you card years ago, and on it was a scene depicting Amish life. Steinbrenner wrote back thanking the couple for the card and fond memories of Ohio it brought back, Becky said.
They still cherish the letter.
Steinbrenner went on to become one of the most powerful owners in professional sports. As his Yankees won -- seven World Series championships and 11 American League pennants in 37 years -- he continued to give to dozens of charities, often stipulating that it be done anonymously.
"He was a good man," Becky said. "I think the media dwelled on his sports background and his temperament, but there was another side to George Steinbrenner. He was a very caring man and he helped an awful lot of people.
"I wouldn't be here without him."
Joe Arnold can be reached at (740) 681-4358 or at jarnold@nncogannett.com.
Source
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