Experts Deem Alcohol Worse Then Crack, Heroin


Drug experts say alcohol worse than crack, heroin


(Reuters) - Alcohol is a more dangerous drug than both crack and heroin when the combined harms to the user and to others are assessed, British scientists said Monday.

Presenting a new scale of drug harm that rates the damage to users themselves and to wider society, the scientists rated alcohol the most harmful overall and almost three times as harmful as cocaine or tobacco.

According to the scale, devised by a group of scientists including Britain's Independent Scientific Committee on Drugs (ISCD) and an expert adviser to the European Monitoring Center for Drugs and Drug Addiction (EMCDDA), heroin and crack cocaine rank as the second and third most harmful drugs.

Ecstasy is only an eighth as harmful as alcohol, according to the scientists' analysis.

Professor David Nutt, chairman of the ISCD, whose work was published in the Lancet medical journal, said the findings showed that "aggressively targeting alcohol harms is a valid and necessary public health strategy."

He said they also showed that current drug classification systems had little relation to the evidence of harm.

Alcohol and tobacco are legal for adults in Britain and many other countries, while drugs such as ecstasy and cannabis and LSD are often illegal and carry the threat of prison sentences.

"It is intriguing to note that the two legal drugs assessed -- alcohol and tobacco -- score in the upper segment of the ranking scale, indicating that legal drugs cause at least as much harm as do illegal substances," Nutt, who was formerly head of the influential British Advisory Council on the Misuse of Drugs (ACMD), said in a statement about the study.

Nutt was forced to quit the ACMD a year ago after publicly criticizing ministers for ignoring scientific advice suggesting cannabis was less harmful than alcohol.

The World Health Organization estimates that risks linked to alcohol cause 2.5 million deaths a year from heart and liver disease, road accidents, suicides and cancer -- accounting for 3.8 percent of all deaths. It is the third leading risk factor for premature death and disabilities worldwide.

In an effort to offer a guide to policy makers in health, policing, and social care, Nutt's team rated drugs using a technique called multicriteria decision analysis (MCDA) which assessed damage according to nine criteria on harm to the user and seven criteria on harm to others.

Harms to the user included things such as drug-specific or drug-related death, damage to health, drug dependence and loss of relationships, while harms to others included crime, environmental damage, family conflict, international damage, economic cost, and damage to community cohesion.

Drugs were then scored out of 100, with 100 given to the most harmful drug and zero indicating no harm at all.

The scientists found alcohol was most harmful, with a score of 72, followed by heroin with 55 and crack with 54.

Among some of the other drugs assessed were crystal meth (33), cocaine (27), tobacco (26), amphetamine or speed (23), cannabis (20), benzodiazepines, such as Valium (15), ketamine (15), methadone (14), mephedrone (13), ecstasy (9), anabolic steroids (9), LSD (7) and magic mushrooms (5).

(Editing by Alison Williams)

http://www.reuters.com/article/idUSTRE6A000O20101101

National Aids Council supplies blood kits to Zimbabwe


Great News !

Firm gets US$595 000 blood kits
Herald Reporter

THE National Blood Transfusion Services of Zimbabwe has received various blood kits worth US$595 000 from the National Aids Council.

The consignment comprises Hepatitis B Reagents Kits (15x2000 test kits), HIV test kits (15x2000 kits), Hepatitis C Reagents kits (15x2000 kits), and syphilis reagents kits (60x500 kits).Officiating at the handover ceremony in Harare last Friday, Health and Child Welfare Minister Henry Madzorera, said the donation ensured that Zimbabwe maintained its standards in blood screening.

"This support is very strategic in that it seeks to ensure that our blood remains safe and that we maintain our record in transfusing safe blood."Ever since, we have never wavered in this effort and our record has remained without blemish," he saidMinister Madzorera said NAC set aside 50 percent of the Aids Levy to support the national ART programme and related interventions.He said the investment in the national response to HIV and Aids by NAC was very vital as it spurred Zimbabwe towards the universal access to HIV and Aids services in line with the World Aids campaign theme for 2009-2011.

Speaking at the same occasion, NAC board chairman Reverend Murombedzi Kuchera said preventing transmission was one of NAC’s priorities, as it was the national co-ordinator to the HIV and Aids response.

http://www.herald.co.zw/inside.aspx?sectid=4389&cat=1

Telaprevir Over Boceprevir?

Related Updates; May 2011
FDA OKs Telaprevir for Hep C; Financial Assistance/Prescribing Information
Vicrelis/Boceprevir IS NOW FDA Approved May 13 2011
Getting Ready; Telaprevir or Boceprevir ?
Updated Daily;
Hepatitis C In The News 
List Of All Articles On;
Telaprevir
Boceprevir

.
Today From Boston (TheStreet) -- Reported on Telaprevir at the American Association for the Study of Liver Disease (AASLD). The article is presented for investors, but has data we all can use.

Adam Feuerstein writes;" Vertex Pharmaceuticals: Telaprevir was the superior hepatitis C drug coming into AASLD and no data or information released over the weekend, including from Merck and its competing drug boceprevir, changed that view. If there's a debate left to have about telaprevir vs. boceprevir in hepatitis C, it's forecasting the market share each drug may garner once both are approved next year".

The investors are waiting for physicians/researchers to see all the data from the phase III studies which will be presented on Monday and Tuesday at the AASLD.

Mr. Feuerstein also remarked on Mercks/boceprevir press released on Saturday. AASLD:Hepatitis C Boceprevir Achieved Significantly Higher Sustained Virologic Response Rates Compared to Control

He wrote they had a lot of statistics but the overall profile of boceprevir was not quite as good as telaprevir. He is waiting for Monday/Tuesday for updates on why the analysis summarized appears to exclude certain patients. He writes " Boceprevir's overall cure rate for treatment-naive Hep C patients ranged from 63-66%, with the proportion of patients eligible for shortened therapy 44%. The cure rate was high (87% for African-American/Blacks and 97% for non-African Americans) for those patients that did receive shortened therapy due to an early and robust response to boceprevir. When these "treatment resistant" patients were re-treated with boceprevir, cure rates ranged from 59% to 66% compared to 21% of patients re-treated with just standard of care.
Vertex has data on telaprevir in similar hard-to-treat patients that is superior to boceprevir, with
cure rates of 65% overall that included patients much more resistant to therapy than those enrolled in Merck's boceprevir study. When similar treatment-resistant patients are compared across both studies, boceprevir's 66% cure rate falls short of telaprevir's 78% cure rate. Vertex is not presenting its telaprevir data in treatment resistant patients at this year's AASLD meeting.

The article also covers Gilead Sciences, and Dr. John McHutchison who has joined the company. Dr. McHutchison gave investors a detailed look at the Hepatitis C drug development efforts. Other drugs were touched on such as RG7128 , IDX184 and TMC435. You may want to go take a look at his article.

http://www.thestreet.com/story/10905966/1/hep-c-update-vertex-merck-and-gilead.html?puc=_tscrss

Video/Liver Updates From Insidermedicine

video

From Saudi Arabia - Extra virgin olive oil protects the liver, according to a report published in Nutrition and Metabolism. Results of an animal study showed that consumption of extra virgin olive oil increased antioxidant enzyme activity consequently reducing oxidative stress on the liver.
From California - BPA exposure may have an effect on semen quality, according to a report published in Fertility and Sterility. Studying over 500 factory workers, researchers found that men with the highest urine BPA levels had up to 4x increased risk of poor semen quality. And finally, from Germany - Research published in the Clinical Journal of the American Society of Nephrology finds an increase in kidney transplants among elderly patients. Researchers found that elderly patients with kidney failure were twice as likely to get a transplant in 2006 when compared to 1995.

Source

Hepatitis C infection and gallstone disease


Also See 2011;
Hepatitis C Cirrhosis: Gallstones and Liver Disease

Pain After Gallbladder Surgery; Sphincter of Oddi (SOD)




Where Is The Gallbladder & What Does It Do?
. 
.It is pretty well surrounded by the liver in the upper right side of the abdomen under the rib cage and has small fluid line called a bile duct connecting it to the liver, pancreas and duodenum. The GB muscle which attaches to the rib cage produces powerful contraction when irritated.

Basically, it's just a sack that holds fluid composed of water, bile salts & cholesterol. When it comes out of the liver it is primarily water. The gallbladder just stores it until 95% of the water is drained away and then ejects it into the duodenum through the bile duct.

However, whether from the liver or gallbladder, bile primarily consists of the following substances: water, bile salts, bilirubin, cholesterol, fatty acids, lecithin, sodium and proteins. If the chemical balance of bile contains too much of any of these components, particularly cholesterol, crystals form and harden into gallstones. Cirrhosis causes the abnormal metabolism of bile pigment. Because of this, gallstones develop twice as often in cirrhosis patients as in those without the disorder. Cirrhosis prevents bile from flowing freely to and from the gallbladder, the bile hardens as gallstones. Cirrhosis poses a major risk for gallstones, particularly pigment gallstones. "Pigment stones are composed of calcium bilirubinate, or calcified bilirubin. Pigment stones can be black or brown, black stones form in the gallbladder and are the more common type. They represent 20% of all gallstones in the U.S. They are more likely to develop in people with hemolytic anemia (a relatively rare anemia in which red blood cells are destroyed) or cirrhosis (scarred liver)". ,

The pain is a result of the gallbladder's large, powerful muscle which is attached to the rib cage, and is contracting in an effort to release bile into the duodenum to neutralize the acid from the stomach. Thus, a stone anywhere in the bile duct, from the liver's exit to the gallbladder's or the pancreas (which shares a common bile duct). Is capable of producing deathlike pain.

The risk factor for women is greater then in men to develop gallstones. In women gallstones occur by the age of 60 in 25% of women and 50% by age 75. Women may be at an increased risk because estrogen stimulates the liver to remove more cholesterol from blood and divert it into the bile. Risk factors in men are about 20% by the age of 75. Because most cases do not have symptoms the rates may be underestimated in elderly men. In people with diabetes there is a higher risk for gallstones and have a higher-than-average risk for acalculous gallbladder disease (without stones). Gallbladder disease may progress more rapidly in patients with diabetes, who tend to have worse infections.

Risk for gallstones are also seen in transplantation, bone marrow, and solid organ transplant. The complications can be so severe that some organ transplant centers require the patients gallbladder be removed before the transplant is performed.

Research has shown that Hepatitis C patients have a greater tendency to develop gallstones. This takes the form of inflammation and pain with or without gallstones causing nausea and possibly vomiting. As a result some people with hepatitis C may have their gallbladder removed. A study in the Journal of Viral Hepatitis last year demonstrated that chronic HCV patients without cirrhosis have an increased prevalence for gallstones.

Data from the 2009 study as published in Medscape :
"Compared with the controls, gallstone disease is present in HCV patients at a younger age and in association with central obesity and liver steatosis, and is not related to gallstone heredity, dyslipidaemia, diabetes mellitus or metabolic syndrome. Although we could not establish a temporal relationship, the association between HCV infection and gallstone disease is real and appears to be causally linked at least in predisposed individuals, namely obese and with liver steatosis".

Video

Gallstones are solid deposits of cholesterol or calcium salts that form in your gallbladder or nearby bile ducts. Complications from gallstones can be serious, and even fatal, if left untreated. Learn about the different causes, symptoms, and treatments of gallstones in this video.


By David King M.D.

Learning about the Gallbladder and Bile System
Anatomy and Function
.

The biliary system essentially consists of the liver, the bile ducts, the gallbladder and the ampulla of Vater. Biles main function is to aid in the absorption and digestion of fats. Bile is made by the liver and then secreted into tiny tubes or ducts in the liver. The bile then travels through these small ducts within the liver, join other ducts within the liver and eventually exiting the liver and becoming one large duct outside called the common hepatic duct. This portion of the bile system is sometimes called the “biliary tree” because the way it resembles a tree with leaves, twigs and branches that eventually all combine to form a common trunk.

The gallbladder is a hollow, pear-shaped, muscular “bag” that has one opening through another duct called the cystic duct. The cystic duct eventually meets the common hepatic duct where they join to form the common bile duct. This duct continues on to join the duodenum (the first part of the small intestine) through a structure called the ampulla of Vater. Within this structure is a muscle “valve” called the sphincter of Oddi which prevents the flow of bile into the small intestine except at specific times.



The liver makes about a quart of bile over the course of an entire day but the body only uses a significant amount of bile when food is present in the duodenum. Because of this, the flow of bile is diverted into the gallbladder during most of the day. Since the gallbladder can only hold about ¼ cup of fluid, it has a remarkable ability to concentrate the bile and reduce its volume by as much as 90%. When food reaches the duodenum after being eaten, the body releases a hormone called cholecystokinin (CCK) which stimulates the sphincter of Oddi to open and the gallbladder wall to contract which squirts the stored, concentrated bile into the duodenum where it mixes with the food to aid in absorption and digestion
.
.Gallbladder Disease

The presence of gallstones is a very common condition that can lead to gallbladder disease. During the concentration of bile, small cholesterol particles can come out of solution and form a layer of sludge within the gallbladder. If this sludge does not get completely evacuated from the gallbladder during contraction it can gradually build up over time. The sludge will usually separate into clumps that eventually become stones. Sometimes many smaller stones are formed and at other times one or two very large stones may form. If these stones become large enough to block the cystic duct when the gallbladder contracts they can inhibit the flow of bile from the gallbladder.



This can lead to the classic symptoms of pain in the right, upper abdomen with associated nausea or vomiting shortly after eating a meal. Since the stones are freely floating within the gallbladder, they may not block the flow of bile with every meal and symptoms may only occur intermittently. If a stone becomes impacted in the neck of the gallbladder, symptoms may become severe and constant requiring urgent intervention to obtain relief. Occasionally, smaller stones may pass through the cystic duct and reach the common bile duct during a gallbladder contraction.

.These stones may pass harmlessly into the small intestine through the ampulla of Vater.

However, if they become impacted at the sphincter of Oddi they can cause life-threatening conditions such as pancreatitis or cholangitis.




Even without the formation of stones, a gallbladder may produce symptoms when it fails to contract properly when stimulated by CCK. A normal gallbladder will eject most of the bile it contains when stimulated. When a gallbladder can only eject 35% or less of its volume with each contraction it is considered diseased. In this condition, the typical gallbladder symptoms of right-sided upper abdominal pain, nausea and vomiting will often be present constantly but with less severity than with gallstones
.
.Diagnosis

.
Gallstones may be diagnosed most easily with ultrasound. Because the stones are higher in density than the surrounding tissue and bile they will absorb or reflect more sound waves leaving a “shadow” on the ultrasound screen. CT scans and plain x-rays will not usually show gallstones unless they contain significant amounts of calcium
.
HIDA Scan

If a patient has typical gallbladder symptoms but their ultrasound does not show any stones a HIDA scan may be ordered. This study involves the placement of an intravenous catheter and injection of a non-harmful radioactive substance that is gathered up by the liver and secreted into the bile. A special type of camera that recognizes radioactive waves is then used to visualize the liver and the gallbladder. Once the gallbladder is full of the radioactive bile, its volume is calculated and a second injection of the hormone CCK is performed through the same intravenous catheter. The volume of the gallbladder is again determined and compared to its full volume. The difference in these two volume measurements is calculated by the physician reading the study and expressed as a percentage number called the ejection fraction. An ejection fraction less than 35% is an indication that the gallbladder is not functioning properly.

Treatment

Many studies have been performed to determine if an effective medical treatment for gallstones exists. A drug was developed that is effective at dissolving gallstones but even when the gallstones were gone most patients still had symptoms. In most cases, the gallstones came back very rapidly after the medication was discontinued. This has lead most physicians to realize that once symptoms occur from gallstones the only proven effective treatment is surgical removal of the gallbladder. However, if gallstones are present but the patient has no symptoms then no intervention is needed in most cases. Surgical removal of the gallbladder remains the mainstay of gallbladder disease treatment. Over the past 15 years, laparoscopy has become the preferred method for gallbladder removal. Today, over 95% of gallbladder removal operations performed in the United States are completed laparoscopically.
Most of these patients go home on the same day as their operation.

Gallbladder Removal Laparoscopic PreOp® Patient Education Feature




For this procedure, a surgeon typically uses 3 or 4 small incisions, a video camera and specialized instruments to remove the gallbladder from the cystic duct and the undersurface of the liver. Since the gallbladder mostly contains fluid, it can usually be removed from the abdomen through an incision no larger than ½ inch. Occasionally, a larger incision must be made when a large stone or multiple stones are present. In a few instances, laparoscopic removal of the gallbladder cannot be performed safely and open surgical technique is required. Sometimes an unanticipated situation or complication found during laparoscopic gallbladder surgery may require conversion to open surgical technique as well.

Open surgery usually requires a longer hospital stay and is typically more painful due to the presence of a large incision. Major complications of gallbladder surgery occur in less than 5% of patients by most recent studies.

Homeopathic

“gallstone-cleansing” techniques have been proclaimed effective and safe by many homeopathic practitioners and lay-people. These treatments usually involve the ingestion of significant quantities of olive oil and citrus juice in an attempt to cause vigorous contraction of the gallbladder to eject all of the stones into the small intestine. Some remedies include a special pectin rich diet for several days before the cleansing which has been shown in some animal studies to soften gallstones. Though these remedies may have been helpful for some people there have been no human studies to confirm its effectiveness or document the risks. Since life-threatening conditions such as pancreatitis and cholangitis can occur with passage of gallstones, these risks should be fully considered before trying any homeopathic remedy.

After Gallbladder Removal

Most patients are eventually able to tolerate any foods they enjoy after their gallbladder has been removed. However, many patients will experience problems such as nausea, bloating and diarrhea with certain foods during the first few months following surgery. A few patients will experience these symptoms regardless of their diet during the first few months following surgery. A small percentage will have these symptoms persist and require significant diet changes, lifestyle modification or medication to manage their condition. Usually fried, greasy or spicy foods tend to cause the most symptoms but any food could become poorly tolerated following gallbladder surgery.


.Other Similar Conditions

Several other different diseases can cause symptoms similar to gallbladder disease. Irritable Bowel Syndrome (IBS), peptic ulcers, gastritis or gastroesophageal reflux disease (GERD) may all mimic symptoms of gallbladder disease. These diagnoses should be considered whenever gallbladder studies are normal but typical symptoms are present.


Conclusion Points 

 
Gallstones are very common. Usually, only symptomatic gallstones need treatment. A poorly functioning gallbladder may also need treatment. Medical or homeopathic treatment has not been proven effective. Most patients are able to lead a normal life without their gallbladder. Surgical removal of the gallbladder is effective and carries a relatively low-risk for most patients.


Gallstones can go unnoticed, but in some cases a stone could cause the gallbladder to become inflamed, resulting in pain, infection, or other serious complications.

Video/Living with Hepatitis C: Viral Load Testing at The Chance Center

Three to four times a year The Chance Center of St. Petersburg, Fl offers free viral load testing for persons with viral hepatitis B & C. This is a video of our Oct. 26,2010 testing day. Over 200 persons in our community received were blessed.

,

November: HCV/HBV Newsletter At HCV Advocate




Alan Franciscus, Editor-in-Chief


Jacques Chambers, CLU


Lucinda Porter, RN

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AASLD 2010 HCV Coverage
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New: Viral Hepatitis and Liver Stages
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Lucinda Porter, RNAlan Franciscus, Editor-in-ChiefHCV Advocate Eblast

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HBV Journal Review
HBV Journal ReviewNovember 1, 2010,

Special "Occult HBV"

Issue:Click Here
.

Vol 7, no 11 by Christine M. Kukka
AASLD 2010 HBV Coverage
.
Action Alert Oct 2010
Hepatitis & Liver CancerAction Alert
.
Follow us on Twitter

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Liver Diseases in Patients With Chronic Hepatitis C Virus Infection

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Prevalence and Challenges of Liver Diseases in Patients With Chronic Hepatitis C Virus Infection
..
Ira M. Jacobson AffiliationsDivision of Gastroenterology and Hepatology and Center for the Study of Hepatitis C, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York
Reprint requests Address requests for reprints to: Ira M. Jacobson, MD, Division of Gastroenterology and Hepatology, Medical Director, Center for the Study of Hepatitis C, Joan and Sanford I. Weill Medical College of Cornell University, 1305 York Avenue, New York, New York 10021. fax: (646) 962-0436, Gary L. Davis
AffiliationsDivision of Hepatology, Baylor Regional Transplant Institute, Baylor University Medical Center, Dallas, Texas, Hashem El–Serag AffiliationsHealth Services Research, Houston Veterans Affairs, Baylor College of Medicine, Houston, Texas, Francesco Negro Affiliations Divisions of Gastroenterology and Hepatology and Division of Clinical Pathology, University Hospital of Geneva, Geneva, Switzerland,
Christian Trépo Affiliations Service de Gastro-entérologie, Service d'Hépatogastroentérologie–Hotel Dieu, Lyon, France
.
published online 16 August 2010.
.
Abbreviations used in this paper:
AASLD, American Association for the Study of Liver Diseases, CHC, chronic hepatitis C, ECC, extrahepatic cholangiocarcinoma, HCC, hepatocellular carcinoma, HIV, human immunodeficiency virus, ICC, intrahepatic cholangiocarcinoma, IDU, injection drug use, IOM, Institute of Medicine, MeSH, Medical Subject Headings, NHANES, National Health and Nutrition Examination Survey, SVR, sustained virologic response
.
Hepatitis C virus (HCV) infections pose a growing challenge to health care systems. Although chronic HCV infection begins as an asymptomatic condition with few short-term effects, it can progress to cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), and death. The rate of new HCV infections is decreasing, yet the number of infected people with complications of the disease is increasing. In the United States, people born between 1945 and 1964 (baby boomers) are developing more complications of infection. Men and African Americans have a higher prevalence of HCV infection. Progression of fibrosis can be accelerated by factors such as older age, duration of HCV infection, sex, and alcohol intake. Furthermore, insulin resistance can cause hepatic steatosis and is associated with fibrosis progression and inflammation. If more effective therapies are not adopted for HCV, more than 1 million patients could develop HCV-related cirrhosis, hepatic decompensation, or HCC by 2020, which will impact the US health care system. It is important to recognize the impact of HCV on liver disease progression and apply new therapeutic strategies.
.
Approximately 180 million people worldwide are infected with hepatitis C virus (HCV)1 and are at risk of developing serious hepatic complications such as cirrhosis, hepatocellular carcinoma (HCC), or decompensation. In the United States, HCV-related end-stage liver disease is the most common indication for transplantation,2 and HCV markers are frequently found in cases of HCC.3, 4 Although some data suggest that hepatitis C does not increase overall mortality,5 it has been postulated that HCV infection could result in an 8- to 12-year reduction in life expectancy.6 It is estimated that HCV caused more than 86,000 deaths in the European region in 2002.7 The prevalence of hepatitis C–related cirrhosis and its complications is expected to continue to increase through the next decade.8 In addition, demographic changes are expected to result in an increasing incidence of severe HCV-related liver disease as the population ages.
Less than half (42%–46%) of patients infected with HCV genotype 1,9, 10 the major genotype in the USA,11 achieve a sustained virologic response (SVR) with currently available treatment (peginterferon/ribavirin for 48 weeks). There is also evidence to suggest that HCV infection is both underdiagnosed and undertreated.12, 13, 14 The lack of access to effective, well-tolerated therapies has serious implications for the current and future burden of HCV. A recent report commissioned by the Institute of Medicine (IOM) of the National Academies highlighted shortcomings in care for viral hepatitis, including the estimate that up to 75% of HCV-infected persons have not even been diagnosed. The report includes sweeping recommendations for prevention, identification, control, and surveillance of HCV in the general population and identifies major gaps in services for specific populations that are disproportionately affected.15
In light of the public health threat posed by HCV, efforts are needed to heighten awareness of its impact on patients. Numerous extrahepatic morbidities are associated with HCV infection; these and their consequences are reviewed elsewhere.16 Here we summarize the latest evidence for the burden of chronic hepatitis C (CHC) in the United States, focusing on hepatic complications.
.
Evidence Acquisition
This review reflects the detailed discussion and opinions of the authors (not the meeting sponsor, Vertex Pharmaceuticals Incorporated) on key articles from the published literature at an advisory board meeting on the burden of liver disease in HCV infection held in Boston, MA, in July 2007. Before the meeting, MEDLINE searches via the PubMed interface were designed and conducted by Paula Michelle del Rosario, a professional medical writer at Gardiner-Caldwell Communications. The searches encompassed the epidemiology and/or burden as a result of HCV-related liver disease by using the Medical Subject Headings (MeSH) [hepatitis C] and either [epidemiology], or [incidence], or [prevalence], or [fibrosis AND epidemiology], or [fibrosis AND mortality], or [liver cirrhosis AND epidemiology], or [liver cirrhosis AND mortality], or [carcinoma, hepatocellular AND epidemiology], or [carcinoma, hepatocellular AND mortality], or [cholangiocarcinoma OR intrahepatic cholangiocarcinoma AND epidemiology], or [fatty liver AND epidemiology], or [fatty liver AND mortality]. Articles not published in the English language and editorials, correspondence, letters, comments, and news articles were excluded. The authors received the search terms and results of the searches in advance of the meeting, and they selected relevant articles for discussion. The authors were responsible for several additions to content and topics covered. Throughout the development of the manuscript, the authors were personally responsible for a marked expansion in the scope of the article, including new references and concepts published since the original advisory board, making this essentially a new article. In addition, the manuscript was thoroughly updated with a repeated PubMed search by Gardiner-Caldwell Communications in September 2009 to capture articles published since the original search was conducted, and relevant publications were selected for inclusion by the authors.
.
Prevalence, Identification of At-Risk Individuals, and Effects on Life Expectancy
Various estimates of HCV prevalence in the US population place the number of infected individuals (as defined by anti-HCV antibody positivity) at between 4.1 and 5 million. Of these, 3.2–3.4 million are chronically infected.17, 18 During the first 10–20 years of infection HCV-infected individuals generally experience asymptomatic or mild illness,19 which explains why an estimated 75% of infections remain undiagnosed in the United States.15, 20 Despite a decline in the number of new US cases of HCV infection from a peak of an estimated 262,000/year in 1986 to 17,000/year in 2007,21 the prevalence of individuals infected with HCV for more than 20 years is expected to continue to increase until 2015.22 In the National Health and Nutrition Examination Survey (NHANES; 1999–2002), patients aged 40–49 years accounted for 66% of American HCV-infected patients, and the prevalence of HCV infection in the United States was 2.7 times higher among 40- to 49-year-olds than the general population (Figure 1).17 This “baby boomer” generation is particularly susceptible to blood-borne HCV transmission as a result of an increased lifetime risk of injection drug use (IDU), blood transfusion before 1992, or sexual activity with ≥20 partners, compared with older or younger patients.23, 24 The prevalence of HCV infection varies by age, sex, and race/ethnicity, and early identification of at-risk individuals through routine questioning by clinicians is critical, because management options are limited in late-stage disease.24
.

Figure 1.
Prevalence of HCV antibodies by age group (A) and year of birth (B) in the 1988–1994 and 1999–2002 NHANES. Vertical bars, 95% confidence intervals.
.

.
Adapted with permission from Armstrong et al 2006.17
After 30 years of infection, an estimated 15%–35% of patients will develop cirrhosis (5-year survival, 75%–80%)6; after 40 years, up to 60% could have cirrhosis. Given the high prevalence of HCV infection among 40- to 49-year-olds17 and that Americans are now expected to live into their mid-70s or beyond, the incidence of complications of HCV infections can be expected to further increase in coming years. In fact, from 1995–2004, US HCV-related mortality already increased 123% from 1.09/100,000 to 2.44/100,000 persons, although this study has some limitations.25 Furthermore, the proportion of CHC patients in the United States with cirrhosis is projected to rise from 25% in 2010 to 45% in 2030.8 Projections also estimate that without effective treatment, the annual number of US patients with cirrhosis, hepatic decompensation, or HCC will roughly double by 2020, and liver-related deaths will almost triple (Table 1).26 Although not all data agree with these estimates,5 several studies have suggested that HCV infection could have a deleterious effect on population mortality rates and life expectancy.27, 28 HCV increased the risk of death in several analyses, irrespective of comorbidities such as coinfection with human immunodeficiency virus (HIV)29 or hepatitis B virus (HBV)30, 31 and even after adjustment for alcohol consumption.32 Furthermore, numerous studies33, 34, 35, 36, 37 and a Cochrane review38 indicated that achievement of an SVR through effective antiviral therapy can significantly reduce mortality in patients with chronic HCV. If all HCV-infected patients were treated with currently available treatment in 2010, liver-related HCV-associated deaths could be reduced by 36% by 2020,8 whereas antiviral treatment rates are currently declining. Improvements in diagnosis and treatment are therefore necessary to reduce the associated public health burden.15, 39
Table 1. Projected Prevalence of HCV Infection and Hepatic Complications in the United StatesReproduced with permission from Davis et al 2003.26
.



.
Hepatic Consequences
Individuals with CHC are at increased risk of liver-related morbidity and mortality. HCV infection was associated with 27% of all US liver transplants performed in 2007,2 and US-based studies demonstrated that up to 51%–55% of HCC patients have anti-HCV antibodies.3, 4 There is also a link between steatosis and liver fibrosis in HCV-infected patients,40 as well as a potential association between HCV infection and HCC or, as described more recently, of intrahepatic cholangiocarcinoma (ICC).41, 42, 43, 44, 45 In some ethnic groups such as Latinos the course of HCV infection is more aggressive, with a higher risk of cirrhosis than other ethnic groups.46 Furthermore, disease progression is more rapid in patients who are coinfected with HCV and HIV. Coinfected patients have approximately double the risk of cirrhosis or decompensation than those infected with HCV alone.47
.
Fibrosis and Cirrhosis
Progressive hepatic fibrosis leading to cirrhosis is the major complication of chronic HCV infection and accounts for almost all HCV-related morbidity and mortality.26 Early studies suggested little, if any, fibrosis progression during the first decade of infection, followed by a slow, regular progression during the next 15 years, increasing to an intermediate rate during the subsequent decade.48, 49 In a German cohort study of 1833 women infected with HCV-contaminated immunoglobulin, 0.5% of patients developed cirrhosis after 25 years.50 Similarly, in a study of 376 HCV-infected women conducted by the Irish Hepatology Research Group, 51% of patients had fibrosis after 17 years, but only 2% had probable/definite cirrhosis.51 These estimates of cirrhosis rates are considerably lower than those from the US multicohort study8 and the widely cited US military study (approximately 35%).5 Fibrosis outcomes of 184 women from the same cohort were followed up for the subsequent 5 years; 49% showed no change in fibrosis, 24% showed regression, and 27% showed progression.52
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Recent data reinforce the potential for severe liver disease to develop in some patients. Among 485 plasma donors infected during the early 1970s, 34% had stage F3/F4 fibrosis (bridging fibrosis), cirrhosis, or HCC after 31 years; their 35-year cumulative survival was 84% versus 91%–95% for the general population.53 Similarly, a study of 300 black and white Americans with untreated HCV infection found that 29% of patients had stage F3/F4 fibrosis after 20 years, and 4.7% had confirmed cirrhosis.54 It should be noted, however, that these studies could have selected patients with severe disease.
The nonlinear progression of fibrosis was recently confirmed in a meta-analysis of 111 HCV studies.55 The mean annual stage-specific transition probabilities were 0.117 for stage F0 to F1, 0.085 for F1 to F2, 0.120 for F2 to F3, and 0.116 for F3 to F4. Although the estimated prevalence of cirrhosis was 16% after 20 years, there was wide variation between studies, suggesting that fibrosis is a highly unpredictable process.
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Infection duration is a major risk factor for severe fibrosis,55 with the progression rate in a 50-year-old being almost 3 times that in a 20-year-old.56 Age at time of infection is also important. In a biopsy analysis of 247 treatment-naïve HCV patients, progression rates were 0.13, 0.14, 0.27, and 0.36 fibrosis units/year for patients aged ≤19, 20–24, 25–36, and >36 years at infection, respectively.57 Age >36 years (vs ≤36 years) at time of infection was independently associated with faster progression. Men infected before age 50 have been identified as comprising the majority of cases of cirrhosis today (73.6%), whereas men aged >50 years when infected have faster disease progression compared with other age groups.8
Several other factors, including sex, baseline fibrosis, HCV genotype, HIV/HBV coinfection, and alcohol consumption, also influence fibrosis progression (Table 2).54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 Identifying these factors can be useful when determining prognosis and advising patients on minimizing liver damage. Indeed, a recent study suggested that HCV genotype 3 might pose a particularly high risk of progressive fibrosis.69 Insulin resistance has been linked with fibrosis,70, 71 and several studies have reported that this relationship remains significant, irrespective of HCV genotype.62, 72, 73 In addition, serum aminotransferase level elevations and the degree of hepatocellular necrosis/inflammation on biopsy have been found to predict fibrosis progression.74 Genetic factors might also play a role in fibrosis progression.75, 76 Recent data indicate that the cirrhosis risk score, which is based on the association of 7 host genes, might help to differentiate HCV patients at high versus low risk of progressing toward cirrhosis, including those with early or mild CHC.76, 77, 78 Steatosis has also been linked to fibrosis progression,40, 67, 79 as has regular cannabis use.68, 80 There is evidence of an association between cigarette smoking and hepatitis fibrosis,81 but not all studies have verified such an association.82
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Table 2. Factors Contributing to Fibrotic Progression in CHC53, 54, 55, 56, 68
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Hepatocellular Carcinoma
The greatest increase in US cancer deaths from 1995–2004 was in those caused by cancers of the liver and bile duct, of which HCC comprised about 76%.83 This might be attributed to the increasing incidence of HCV-related HCC because rates for HBV-related and alcohol-related HCC have remained stable during recent years.84, 85 The incidence of HCV-related HCC in the United States is projected to peak in 2019 at 14,000 cases/year.8 In a large US database, the proportion of HCV-related cases of HCC among HCC patients aged ≥65 years doubled from 11% in 1993–1996 to 21% in 1996–1999.84 During the past decade, the fastest increase in HCC incidence has affected Hispanics and whites.86 In multivariate analysis HCV infection was an independent predictor for the development of HCC.87 Furthermore, maintenance therapy with peginterferon did not reduce the 5-year incidence of HCC in the HALT-C cohort.88
Comparisons of US and Japanese HCV strains suggest that the US HCV epidemic began about 2 to 3 decades after that in Japan.89, 90 This has led to speculation that the burden of HCC in the United States might eventually equal that currently seen in Japan as HCV-infected individuals age and their infection duration increases. In Japan, HCV-related HCC accounts for 80% of all HCC cases,91 and the rate of HCC among HCV-infected men has risen from 17.4/100,000 in 1972–1976 (32,335 deaths) to 27.4/100,000 in 1992–1996 (109,365 deaths).92
A recent Italian study of 214 HCV-infected patients with Child–Pugh class A cirrhosis showed that HCC developed at a rate of almost 4%/year.93 HCC was the first complication to occur in 55 (27%) patients; after 17 years, HCC had developed in 68 (32%) patients.93 In another cohort of 416 patients with uncomplicated Child–Pugh class A HCV-related cirrhosis, the incidence of HCC was 13.4% at 5 years, and the 5-year HCC death rate was 15.3%, with the hazard rate of HCC tending to increase over time.94
Several factors influence the risk of HCC in patients with HCV-related cirrhosis. Generally, HCC risk is increased in patients aged >50 years or those infected when aged >50 years, patients with longer duration of infection, men, overweight or diabetic patients, and patients with advanced cirrhosis or elevated alpha-fetoprotein.8, 95, 96 Other possible risk factors include the presence of steatosis,41 HCV genotype 1b,97 Asian/African American race,98 and occult HBV infection.99 As for hepatic fibrosis, an association between cigarette smoking and HCV-related HCC has been suggested in some studies100 but not others.101
Chronic HCV-related inflammation might increase HCC risk by shifting hepatocytic transforming growth factor–beta signaling from tumor suppression to fibrogenesis.102 HCC generally develops after cirrhosis is established, signifying the likely importance of long-standing necrosis and regeneration, an environment of extensive scarring, in its pathogenesis. HCV might influence hepatocarcinogenesis through the oncogenic effects of its core protein, which might augment oxidative stress.103 It might also alter the signaling cascade of mitogen-activated protein kinase and activating factor 1, thereby activating cell-cycle control. Liver angiogenesis and the neovascular response,104, 105 plus genomic changes that deregulate components of the Jak/STAT pathway in early carcinogenesis,106 might also promote HCV-related hepatocarcinogenesis. Additional mechanisms have also been proposed.107
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Cholangiocarcinoma
Various small studies have demonstrated a link between HCV and ICC.42, 43, 44, 45 A recent large cohort study of >140,000 HCV-infected military veterans108 showed a >2-fold increase in ICC risk in HCV-infected patients versus noninfected controls. However, many of these hospital-based, case-control studies are limited by the potential for selection or ascertainment bias,108 and some studies have failed to observe any association between HCV and ICC.109, 110 The association of HCV infection with susceptibility to ICC, and the pathogenetic basis for such an association, warrant further investigation. Chronic HCV infection was not a risk for extrahepatic cholangiocarcinoma (ECC).111
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Decompensation
Patients with HCV-associated cirrhosis are at high risk of developing hepatic decompensation, manifesting as hepatic synthetic dysfunction or complications of portal hypertension. Clinical signs of decompensation include ascites, encephalopathy, and upper gastrointestinal hemorrhage caused by variceal bleeding.93, 112
In an analysis of data from 1000 HCV patients with mild to advanced fibrosis, the incidence of decompensated cirrhosis after 5–7 years of follow-up was 43.5/10,000 person-years or about 1 in 230 patients/year.65 Similarly, a retrospective study reported the 5-year risk of decompensation to be 18% in 384 HCV patients with compensated cirrhosis (incidence, 3.9%/year),112 and a recent estimate suggests decompensation is currently present in 11.7% of CHC patients with cirrhosis.8 Decompensation has become more common since 1995, and because the proportion of CHC patients with cirrhosis is expected to increase through 2030, the incidence of decompensation can be expected to increase accordingly.8 It should be noted, however, that this model estimates that the majority of cirrhotic patients with chronic HCV infection will not develop decompensation during the first 3 decades of infection. Annual incidence rates for ascites (2.9%), jaundice (2.0%), upper gastrointestinal bleeding (0.7%), and encephalopathy (0.1%) were established in a later prospective study of 214 HCV-RNA seropositive patients after 114 months of follow-up.93
Age at HCV acquisition is relevant, with decompensation risk as high as 133/10,000 person-years in patients infected after 39 years of age.65 In addition, the presence of the human leukocyte antigen DRB1*1201–3 allele might be associated with a higher rate of progression toward decompensated cirrhosis and HCC.65 The identification of reliable proteomic/genomic markers for risk of advanced HCV-related liver disease would aid prognostication and therapeutic decision-making.
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Steatosis
Steatosis occurs to some degree in about half of all patients with chronic HCV infection.40, 113 In a meta-analysis of data from >3000 patients, steatosis was independently associated with the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, overweight (body mass index >25), age ≥45 years, and genotype 3 infection.40 Among 101 HCV-infected patients with no factors predisposing to fatty liver, steatosis was found in 41% of patients, irrespective of sex, age, or infection route.114
Two main mechanisms underlie the pathogenesis of steatosis in HCV-infected patients who abstain from alcohol, a direct viral effect and a metabolic mechanism. Viral steatosis is associated with genotype 3 HCV infection,40, 114, 115, 116, 117 where the severity of steatosis correlates with serum71, 115 and intrahepatic113 viral load. This type of steatosis often resolves after viral eradication.116, 117, 118 It is believed that HCV genotype 3 has a direct effect on hepatocyte lipid metabolism, resulting in fat accumulation. Interactions involving the HCV genotype 3 core protein, such as enhanced fatty acid synthase promoter activation119 and increased lipid affinity,120 are being investigated in vitro.
Metabolic steatosis is seen primarily in patients infected with genotype non-3 HCV40, 72 and is largely due to insulin resistance,62, 72, 121 characterized by hyperinsulinemia and free fatty acid overflow to organs and non-adipose tissues.122 These alterations give rise to triglyceride accumulation in hepatocytes, resulting in steatosis.40, 70, 71, 123
Steatosis might reduce the likelihood of achieving SVR with HCV treatment, even when other steatosis-inducing factors are accounted for. In one study, SVR rates were 18%–32% lower in people with steatosis versus those without steatosis after adjusting for other potentially confounding cofactors such as genotype, fibrosis score, and viral load.117
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Reducing the Impact of Infection
About 85% of HCV-positive persons in the United States general population can be identified on the basis of 3 characteristics: IDU history, blood transfusion before 1992, or abnormal serum alanine transaminase levels.17 In selected populations, other characteristics might also be useful for screening. A retrospective study of 5400 US veterans found that the following factors predicted HCV infection: IDU, blood transfusion before 1992, service during the Vietnam war, tattoo, and a history of abnormal liver test results.123 However, HCV risk factor histories are rarely documented in clinical practice.124 Infected patients can thus remain undiagnosed until they present with hepatic complications. Recent guidelines issued by the American Association for the Study of Liver Diseases (AASLD) make recommendations for diagnosis and counseling of HCV-infected patients on alcohol, weight loss, and treatment to prevent the development of cirrhosis and other complications.125
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Diagnosis and Screening
Figure 2 summarizes the clinical management of patients at risk of HCV infection. Asking patients about their transfusion history and high-risk drug/sexual behavior during health care visits should be routine, and high-risk patients (history of IDU, blood transfusion before 1992, or HIV-positive) should be tested, with cognizance of the higher prevalence rates in men, “baby boomers,” and African Americans. The AASLD guidelines promote screening in at-risk populations to reduce HCV transmission rates.125 The recent IOM report on viral hepatitis includes a recommendation that federally funded US health care insurers improve access to HCV screening as part of preventative care for the general population, so people at risk of HCV infection can be identified.15

Figure 2.
Summary of the screening, diagnosis, and treatment of patients at risk of HCV infection.




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Once diagnosed, patients should be evaluated for HCV RNA, genotype, and serologic exclusion of common liver diseases. Baseline imaging (ultrasound) might also be useful. Assessing fibrosis by liver biopsy can be used to estimate prognosis, treatment urgency, and necessity of HCC screening. Surrogate methods, including serum fibrosis markers, imaging techniques, and indirect methods to measure liver stiffness such as transient elastography,125 might have a future role.
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Because insulin resistance enhances fibrosis progression, monitoring insulin resistance, fasting glucose, or insulin levels is advisable. In addition, lifestyle modifications, including weight loss and dietary changes, might reduce insulin resistance and slow the fibrosis rate. All patients should be assessed for immunity against hepatitis A/B by assessment of disease markers and vaccinated if seronegative.125 Counseling should be offered regarding alcohol consumption, if appropriate.
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Treatment
Currently, the only drugs available to treat HCV are peginterferon and ribavirin. SVR rates associated with peginterferon/ribavirin are suboptimal, particularly for genotype 1–infected patients.9, 10 The AASLD guidelines recommend an individualized treatment approach based on assessment of comorbidities, likelihood of response, and side-effect potential.125 Although more effective options are needed, successful treatment can eradicate the virus and thereby minimize complications and possibly improve mortality rates.126, 127 Nearly all patients (99.2%) maintain undetectable HCV loads 5 years after attaining SVR, representing a “virologic cure.”126 Some patients with fibrosis who achieve SVR demonstrate an improvement in necroinflammatory activity and fibrosis regression.128, 129, 130 Furthermore, the 5-year survival of SVR patients is similar to that of the overall population.130 The role of interferon in preventing HCC is controversial. A reduced risk of HCC has been noted in patients achieving SVR; however, reports of HCC after SVR was achieved in cirrhotic patients indicate a need for surveillance and reinforce the importance of viral eradication before cirrhosis develops.131, 132 Long-term maintenance therapy with peginterferon does not appear to affect the incidence of HCC.133
Davis et al8 extended their multicohort model to include an assessment of treatment effects, predicting that an increase in the proportion of treated patients (or use of treatment with improved viral clearance rate) would result in reduced rates of cirrhosis, liver failure, HCC, and liver-related death.
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Also See On This Blog : Oct 30 2010/Many Have A New Chance At Treating Hepatitis C
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..
Education and Counseling
A lack of knowledge about HCV among health care providers, social service providers, and the public is identified by the IOM as a major challenge to controlling the disease. Education and outreach programs for these audiences feature among the recent IOM recommendations for comprehensive viral hepatitis services aimed at preventing viral transmission, missed diagnosis, and poor health outcomes in HCV.15
Increasing access to treatment and providing support to optimize therapeutic adherence might help to improve outcomes. This requires a greater emphasis on early detection along with careful, individualized diagnostic assessment and therapeutic decision-making. Many physicians have adopted a “watch-and-wait” approach, particularly for patients with minimal liver disease. Although this might sometimes be appropriate, patients should be advised of the possibility of unexpectedly rapid disease progression and the need for regular follow-up, including repeat biopsies every 3–5 years. The pros and cons of deferring therapy should be discussed in the context of the patient's clinical and histologic profile.
Many eligible patients decline antiviral treatment. In a study of 280 US patients, 41% declined treatment, citing no symptoms and concerns about side effects.134 Information provided by health care providers is critical; in 3 US cities, interest in HCV treatment among injection drug users was 7-fold higher among patients who were told that they were at risk for cirrhosis or cancer.135 Patients under regular review are also more likely to be interested in receiving treatment,135 emphasizing the importance of communication and continuity of care. Several promising agents, including HCV protease and polymerase inhibitors (eg, telaprevir, boceprevir, and R7128), are in phase 2 or phase 3 trials, with a hope of availability within 2–3 years and beyond.
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Changing Our Views
The impact of HCV infection on the burden of liver disease is becoming evident as individuals unknowingly infected decades ago age and develop severe sequelae of advanced liver fibrosis. Up to 1 million Americans are predicted to develop HCV-related hepatic complications during the next 2 decades.26 Persons born between the 1940s and 1960s account for most infections, with the highest risk among those with a history of IDU or blood transfusions before 1992. Once chronic infection is established, disease progression is variable and dependent on several factors. Cirrhosis, liver failure, and HCC might occur at a faster rate and in more patients than previously believed.
HCV infection is a health care priority. Increasing access to treatment might significantly reduce the morbidity and mortality burden of HCV infection.136 Other measures to tackle the challenge of HCV include improving surveillance, screening and identifying patients at risk of progression, and optimizing therapy. We now need to capitalize on what we know about HCV and formulate strategies to address the anticipated surge in HCV-related morbidity and mortality. New HCV treatments are in development that might increase SVR and potentially decrease the burden of hepatic complications in populations with significant unmet need.
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Acknowledgments
This review is based partially on studies identified and discussed by the authors during an advisory board meeting sponsored by Vertex Pharmaceuticals Incorporated in 2007. The authors would like to thank Dr Miriam Alter for her valuable discussion during the meeting and Paula Michelle del Rosario, MD, and Magdy Fahmy, PhD, of Gardiner-Caldwell Communications, Macclesfield, UK (supported by Vertex Pharmaceuticals Incorporated) for designing and conducting the PubMed literature search and for their professional medical writing assistance in developing the first draft of the manuscript, based on our recommendations of relevant published papers and our debate and discussion during the meeting.
All authors provided close direction to the medical writers, including significant content additions and redrafts, and commented on each version of the manuscript. Author revisions and comments were collated by Gardiner-Caldwell Communications. All authors substantially contributed to development of the manuscript and have read and approved the final draft. The corresponding author had full access to the source literature and takes full responsibility for the content of the paper.

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This article has an accompanying continuing medical education activity on page e117. Learning Objectives—At the end of this activity, the learner should be able to appreciate the prevalence of HCV virus infection in the United States as well as worldwide, understand the natural history of HCV infection, including the long-term risk of cirrhosis and hepatocellular cancer, and recognize that a sustained viral response represents a virologic cure.
Conflicts of Interest The authors disclose the following: Ira M Jacobson is a consultant for Abbott, Anadys, Boehringer Ingelheim, Bristol-Meyers Sqibb, Genetech, Gilead Sciences, GlobeImmune, Human Genome Sciences, Merck, Novartis, Pfizer, Pharmasset, Tibotec, Zymogenetics, and Vertex Pharmaceuticals (including advisory board for manuscript); an investigator for Abbott, Anadys, Boehringer Ingelheim, Genetech, Gilead Sciences, GlobeImmune, Human Genome Sciences, Idenix, Merck, Novartis, Pfizer, Pharmasset, Tibotec, Vertex Pharmaceuticals, and Zymogenetics; and a speaker for Bristol-Myers Squibb, Genetech, Gilead Sciences, Merck, and Novartis. Gary L. Davis is an investigator and consultant (including advisory board for manuscript) for Vertex Pharmaceuticals and receives research funding from Human Genome Science, Merck, Roche, Schering-Plough, and Vertex Pharmaceuticals. Hashem El-Serag is a consultant for Vertex Pharmaceuticals (including advisory board for manuscript). Francesco Negro is a consultant for Vertex Pharmaceuticals (including advisory board for manuscript) and receives educational grant support from Roche. Christian Trépo is an investigator and consultant for Vertex Pharmaceuticals (including advisory board for manuscript).
Funding This report is based on material identified by the authors during an advisory board meeting conducted by Vertex Pharmaceuticals Incorporated.
PII: S1542-3565(10)00780-9
doi:10.1016/j.cgh.2010.06.032