Hepatitis C, a leading killer, is frequently undiagnosed but often curable

20 march 2012-- Hepatitis C virus — not AIDS-causing HIV — is the leading chronic virus infection leading to death in the United States, and its victims most often are baby boomers. More than half who are infected do not know it.

Researchers from the U.S. Centers for Disease Control and Prevention (CDC) found in a study published in the February 21 issue of the Annals of Internal Medicine that hepatitis C had overtaken HIV as a cause of death in the United States by 2007.

Deaths in the United States due to HIV infection have been steadily decreasing, and dropped below 13,000 in 2007, while deaths from hepatitis C infection have been steadily increasing, first surpassing 15,000 per year in 2007.

The good news, according to UCSF liver specialist Alex Monto, MD, is that there has been progress in fighting both diseases, and the kinds of drug combination strategies that have done so much to transform HIV infection from a death sentence to a manageable disease are poised to further boost cure rates for those infected with hepatitis C.

“We know that not enough people with risk factors get tested,” Monto says. “There are a lot of people walking around with hepatitis C who don’t know it.”

Monto directs the liver clinic at the UCSF-affiliated San Francisco Veteran’s Affairs Medical Center, one of four hepatitis C centers nationally within the VA system. Like boomers, veterans are disproportionately affected by hepatitis C. The VA cares for 165,000 patients who are chronically infected with the virus.

Three Million in U.S. Diagnosed with Hep C

Chronic Hepatitis C has been diagnosed in about three million people in the United States. It often causes no symptoms, and many who have been infected for years or even decades may remain unaware of it until symptoms finally appear. The ultimate cause of death attributable to chronic infection is cirrhosis or liver cancer, although the disease progresses to cirrhosis in fewer than half of cases. There is no vaccine.

“The main risk factor in the United States is past injection-drug use,” Monto says. “The others most at risk are those who received blood transfusions before 1992,” Monto says, referring to the year when high-quality screening of the blood supply was implemented.

Compared to HIV or hepatitis B, the risk of hepatitis C being transmitted by sex is low, Monto says, but among men who have sex with men there has been an increase in reports of the virus being sexually transmitted, more so among those who are infected with HIV.

“Anybody with a history of ever being exposed to injection drugs or who received a transfusion before the blood supply was screened should be tested,” Monto says. “That’s not controversial at all. What has been controversial is whether or not all baby boomers should be screened.”

Another study in this week’s edition of the journal suggests that a one-time blood test ordered by primary care providers to screen for antibodies to hepatitis C in those born between 1945 and 1965 would be cost effective — costing $2,874 for each chronically infected patient identified — and would lead to the identification of more than 800,000 previously undiagnosed cases.

Those who are chronically infected may be able to reduce the likelihood of disease progression by avoiding alcohol, by maintaining a healthy weight, and by being vaccinated against hepatitis A and hepatitis B, Monto says.

Treatment Often Cures Hepatitis C

About four out of five who are infected do not rid themselves of the virus without treatment. For about a decade the standard treatment was a combination of two drugs — pegylated interferon given once per week by subcutaneous injection, and daily ribavirin pills, with treatment lasting from six to 11 months. This treatment represented a vast improvement — offering cure rates of 40 percent to 50 percent in most patients, according to Monto.

Within the past year two new drugs of a type known as protease inhibitors have become available. These are valuable for the 75 percent of U.S. hepatitis C patients infected with a form of the virus called genotype 1. With the protease inhibitors added to the mix, the duration of treatment may be shorter, and the cure rate has increased to about 70 percent in patients who have not previously been treated, Monto says. A cure may be less likely for those who have been previously treated, depending on how they responded to earlier treatment.

“New therapies are clearly getting better, and there are probably 25 to 30 new drugs in the pipeline, with many coming out in the next few years,” Monto says. “There are going to be drugs that are better than the ones we have so far.” Several UCSF researchers, including Monto, are helping to evaluate new drugs in clinical trials. UCSF researchers also are investigating the role of the immune system in hepatitis C and hepatitis B infection.

Not to Be Confused with Hepatitis B

Hepatitis B chronically infects about half as many as hepatitis C in the United States, and hits those of Asian descent especially hard — they account for half of hepatitis B infections. Hepatitis B is responsible for about 1,800 deaths yearly in the United States.

Despite the similar names, the two viruses are not closely related. Hepatitis B is spread much more easily through sexual intercourse, and passes from mother to newborn child much more easily. In most adults who become infected the immune system successfully controls infection. Only about five percent of adults exposed to hepatitis B become chronically infected, according to Monto.

There are vaccines for hepatitis B. A UCSF laboratory team led by William Rutter, PhD, now professor emeritus, first demonstrated that an uncontaminated source of material for a hepatitis B vaccine could be obtained by mass-producing viral proteins in genetically engineered, laboratory-grown yeast. This was the groundwork leading to the first marketed genetically engineered vaccine, made by Chiron, a company co-founded by Rutter.

Provided by University of California, San Francisco

Extended Drug Therapy for Hepatitis Is Challenged

By RONI CARYN RABIN
05 dec 2008--Patients who do not initially respond to standard drug therapy for treatment of hepatitis C are unlikely to respond to long-term maintenance therapy as well, according to a new study.
Yet many patients who do not at first respond to drugs are placed on maintenance therapy, which is expensive and can be both physically and psychologically grueling, in hopes that long-term treatment will keep the disease in check. The practice is ineffective and possibly harmful, the study’s authors said.
“To the extent there are still patients out there who are on this form of maintenance therapy, there is a real take-home message: It should be stopped,” said the lead author, Dr. Adrian M. Di Bisceglie, professor of internal medicine and co-director of the liver center at St. Louis University School of Medicine.
The maintenance therapy failed despite the fact that it was effective at lowering the amount of virus in patients’ blood and reducing conventional signs of liver damage, Dr. Di Bisceglie said.
The report appears in Thursday’s issue of The New England Journal of Medicine.
The standard treatment for hepatitis C is a regimen of two potent drugs, peginterferon and ribavirin, that can produce side effects like fever, debilitating fatigue and depression. But the treatment clears the virus from the body in about half of all patients.
Those who do not respond to the initial one-two punch in six months to a year are often advised to continue with a lower, maintenance dose of peginterferon alone for an indefinite period.
The new study, conducted at multiple medical centers and supported by the National Institute of Diabetes and Digestive and Kidney Diseases, followed 1,050 patients with advanced liver disease who had failed to respond to initial treatment for three and a half years. Most of the subjects were men, and their mean age was 51. About half received low doses of peginterferon, while half received no therapy.
Patients on long-term peginterferon fared just as poorly as nonresponders who were not taking the drug, the investigators found.
About a third in each group developed serious complications of hepatitis C, like liver cancer and liver failure.
Eight patients on peginterferon died, compared with two who were not taking the drug, a statistically significant difference, researchers said.
“This is a treatment that should not be done,” said Dr. Howard Worman, professor of medicine at Columbia University College of Physicians and Surgeons, who was not involved in the study. “Patients should just sit tight and wait for new treatments or drugs to be added, which will happen within a few years.”
Dr. David Bernstein, chief of gastroenterology and hepatology at North Shore University Hospital on Long Island, said there might still be a “glimmer of hope,” though very little evidence, that some hepatitis C patients who failed the initial course of treatment might benefit from extended maintenance treatment.
But for now, Dr. Bernstein added, “there’s no reason to make someone feel sicker than they generally feel.”

Diabetes Boosts Liver Cancer Risk in Hepatitis, Cirrhosis Cases

06 june 21008 -- Diabetes doubles the risk of liver cancer in patients with chronic hepatitis C with advanced fibrosis, or cirrhosis, a Dutch study reports.
Researchers at the Erasmus MC University Medical Center in Rotterdam analyzed data on 541 European and Canadian patients with chronic hepatitis C with advanced cirrhosis. Of those patients, 85 had diabetes. Patients with more severe fibrosis were more likely to have diabetes.
"The prevalence of diabetes mellitus was 10.5 percent for patients with Ishak fibrosis score 4, 12.5 percent for Ishak-score 5 and 19.1 percent for Ishak-score 6," the researchers wrote.
The patients were followed for a median of four years. During that time, 11 patients with diabetes and 27 patients without diabetes developed liver cancer. The five-year liver cancer occurrence rate was 11.4 percent and 5.0 percent, respectively. The study also found that being male and older were significantly associated with increased risk of liver cancer.
Among patients with diabetes, there was a trend toward higher liver cancer risk as fasting glucose levels increased, which suggests that hyperinsulinemia might explain the increased liver cancer risk among diabetic patients, the study authors suggested.
Whatever the mechanism, it's clear that diabetes increases the risk of liver cancer in patients with chronic hepatitis C and advanced cirrhosis, the researchers concluded.
The study was published in the June issue of the journal Hepatology.

AASLD: Maintenance Therapy for Chronic Hepatitis C Found Ineffective


BOSTON, Nov. 8 -- Long-term maintenance therapy with peginterferon did not reduce the rate of chronic hepatitis C progression and advanced hepatic fibrosis for patients refractory to other treatment.The peginterferon patients had previously been treated with peginterferon-ribavirin. After 3.5 years, 34.1% of the peginterferon group and 33.8% of the control group had evidence of disease progression, (hazard ratio: 1.01, 95% CI: 0.81 to 1.26, P=0.91), said Adrian M. Di Bisceglie, M.D., of St. Louis University.
Action Points
Explain to patients with chronic hepatitis and advanced fibrosis who have not responded well to initial peginterferon-ribavirin therapy that according to this study continuing treatment with peginterferon does not appear to be beneficial.
This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary as they have not yet been reviewed and published in a peer-reviewed publication.
Dr. Di Bisceglie reported results of the long-awaited 1,050-patient HALT-C (Hepatitis C Antiviral Long-Term Treatment against Cirrhosis) trial at a late-breaking trials plenary session of the American Association for the Study of Liver Diseases meeting here.
He said there was no significant difference in the rates of any of the components of the primary outcome -- death, hepatocellular carcinoma, liver decompensation, and increase in fibrosis -- between the peginterferon patients and the control patients.
Interestingly, mean serum alanine aminotransferase (ALT) and HCV RNA levels decreased significantly with treatment (both P0.0001), as did necroinflammatory changes on liver biopsy (P0.0001).
The HALT-C findings on surrogate markers mirrored results from earlier small trials of long-term peginterferon therapy -- results that led many to assume the strategy would be effective, said Ira Jacobson, M.D., chief of gastroenterology and hepatology at Cornell Weill Medical College in New York.
Dr. Jacobson, who was not involved in the trial, said, despite the suggestion of a trend toward improvement in fibrosis and less inflammation in an earlier study, "that improvement did not translate into improvement in progression of fibrosis or improvement in major clinical outcomes. I found it particularly notable that [maintenance therapy] did not seem to be associated with a reduction in hepatocellular carcinoma, the single most prevalent complication in patients with chronic HCV."
He said that the finding will not have an impact in his practice because "I was not using maintenance therapy pending the outcome of this very important trial, the findings of which have vindicated those of us who have not widely applied maintenance therapy."
Dr. Di Bisceglie agreed that the surrogate markers did not have clinical meaning in this study. He also said that eradication of HCV should continue to be the gold standard of treatment.
The trial randomized 517 patients to peginterferon alfa-2a (90 mcg per week) and 533 to placebo. All patients had chronic HCV infection with an Ishak fibrosis score of ≧3 on liver biopsy, a Child-Turcotte-Pugh score of ≦6, no history of ascites, encephalopathy or bleeding varices, and no other identifiable cause of liver disease.
Patients were stratified according to their stage of fibrosis: Ishak stage 3 or 4 (622 with fibrosis) versus stage 5 or 6 (428 with cirrhosis). In order to be monitored for disease progression, the participants were seen at three-month intervals, and underwent liver biopsy at 1.5 and 3.5 years after randomization.
For the primary outcomes, 6.6% of the treatment group died compared with 4.6% of the placebo controls; there was decompensation in 14.3% of the treatment group compared with 13.2% of controls; hepatocellular carcinoma developed in 2.8% of the treatment group compared with 3.2% of controls; and there was an increase in fibrosis in 28.2% of the treatment group compared with 31.9% of controls. None of the differences was statistically significant.
The rate of serious events was about one-third of each group. With regard to patient compliance, 53% were still on a full dose of treatment at 3.5 years, 10% were on a lower dose, and 37% stopped therapy, said Dr. Di Bisceglie.
The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases and by Roche. Dr. Di Bisceglie has a financial relationship with Roche.
Primary source: American Association for the Study of Liver DiseasesSource reference: Di Bisceglie AM, et al "Prolonged Antiviral Therapy With Peginterferon to Prevent Complications of Advanced Liver Disease Associated With Hepatitis C: Results of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial" AASLD Meeting 2007; Abstract LB1 presented Nov. 5.

ACG: Gene Expression Predicts Sustained Response in Chronic Hepatitis C

PHILADELPHIA, Oct. 18 -- A panel of gene expression biomarkers can identify patients with chronic hepatitis C genotype 1 who are likely to achieve sustained virologic response to interferon-based therapy, results of a study reported here suggest.
Within seven days after the start of treatment, the gene expression panel had a sensitivity of 100% within 24 hours and a specificity of 92% for sustained virologic response, Zobair Younossi, M.D., of Inova Fairfax Hospital in Falls Church, Va., told attendees at the American College of Gastroenterology.
The biomarkers predicted response independent of conventional prognostic factors such as obesity and ethnicity, he added.
An estimated 75% to 80% of patients infected with HCV in the United States are genotype 1, which tends to confer the greatest resistance to treatment. Conventional clinical, demographic, and environmental prognostic factors have fairly limited utility for early identification of patients who will respond to treatment.
Dr. Younossi and colleagues performed mRNA profiling using six housekeeping genes and 317 mRNA transcripts from 160 genes. They performed logistic regression analysis to identify genes associated with response to therapy. They also evaluated patterns of gene expression in patients before and during treatment.
The researchers then developed predictive models that they applied to 44 patients chronically infected with HCV genotype 1. The study group comprised 19 treatment-naive patients and 25 who had not responded to prior therapy. Gene expression patterns were evaluated in each patient at baseline and then at days one, seven, 28, and 56.
Dr. Younossi reported data from analyses of gene expression models for predicting sustained virologic response before treatment, 24 hours after initiation of treatment, and seven days after starting treatment. Treatment consisted of pegylated interferon-alfa plus ribavirin.
In the treatment-naive cohort, a two-gene panel consisting of EP300 and SOC56 had a sensitivity of 86% and a specificity of 91% for predicting response before treatment.
During the first 24 hours after initiation of treatment, the combination of IL1B and ADAM9 yielded a sensitivity of 86% and a specificity of 91% for sustained virologic response.
At seven days a model focusing on changes in expression of PRKRIR yielded a sensitivity of 100% and a specificity of 75%.
Dr. Younossi said pretreatment gene expression in the treatment-experienced patients included upregulation of IFR-2 a negative regulator of interferon signaling. After initiation of therapy, changes in activity were observed in a variety of signaling cascades involved in apoptosis, proliferation, and lymphocyte metabolism.
IRF-2 provided the best pretreatment prognostic accuracy for the treatment-experienced patients. The model had a sensitivity of 62.5% and a specificity of 87.5%.
At 24 hours after the start of treatment, a model derived from expression patterns of two genes-IFIT2 and JAK1-resulted in a sensitivity of 100% and a specificity of 75%.
At seven days, a six-gene panel had a sensitivity of 100% and a specificity of 92.3% for predicting sustained virologic response.
Although the results are promising, Dr. Younossi said the prognostic strategy requires validation in additional studies involving more patients.
Dr. Younossi disclosed no conflicts. The study was supported by Celera Diagnostics in Alameda, Calif., and several of the investigators are Celera employees. Primary source: American College of GastroenterologySource reference: Yousonni Z et al. "Gene expression biomarkers can predict sustained virologic response early after initiation of pegylated interferon alfa and ribavirin in patients with genotype 1 chronic hepatitis C." American College of Gastroenterology Annual Meeting and Postgraduate Course. Oct. 12-17, 2007. Philadelphia. Abstract 29.