October 28, 2013

Hepatitis C Drug Sofosbuvir Still Effective at 24 Weeks

Medscape Medical News > Conference News

Jim Kling

October 28, 2013

SAN DIEGO, California — New data from 4 phase 3 trials with the hepatitis C (HCV) drug sofosbuvir (SOF) and ribavirin (RBV) show that a 12-week regimen is effective in treating HCV genotypes 1 through 6. Twenty-four-week sustained virologic response (SVR) is essentially identical to 12-week SVR, bolstering confidence that the drug combination represents a cure. Those with genotype 3 infections are better served with a 16-week course of treatment.

The new work extends the results of the studies out to 24 weeks after treatment cessation. Twenty-four weeks was the traditional milestone for HCV treatments, but in recent years, the US Food and Drug Administration and industry have gravitated toward the 12-week time point. However, with new drugs set to greatly affect HCV treatment, it is important to consider this older benchmark, according to Kris Kowdley, MD, director of the Liver Center of Excellence at the Digestive Disease Institute at the Virginia Mason Medical Center in Seattle, Washington, who presented the research here at the American College of Gastroenterology (ACG) 2013 Annual Scientific Meeting and Postgraduate Course.

"We're in a brave new world of hepatitis C treatments, and we're very quickly reaching all oral, interferon-free, short-duration regimens, so I think it remains valuable to continue following patients to 24 weeks, and possibly 48 weeks, posttreatment to see if the assumption [of a cure] really holds up. We can also learn more about late relapses and possible questions about resistance," Dr. Kowdley told Medscape Medical News.

The research drew from 4 phase 3 studies: Sofosbuvir With Peginterferon Alfa 2a and Ribavirin for 12 Weeks in Treatment-Naive Subjects With Chronic Genotype 1, 4, 5, or 6 HCV Infection (NEUTRINO), which enrolled treatment-naive patients with genotype (GT) 1, 4, 5, and 6 infection, each of whom received 12 weeks of SOF, peg-interferon (PEG), and ribavirin (RBV); Phase 3 Study of Sofosbuvir and Ribavirin (FISSION), which enrolled treatment-naive GT 2/3 patients to receive either 12 weeks of SOF+RBV or 24 weeks of PEG+RBV; GS-7977 + Ribavirin for 12 Weeks in Subjects With Chronic Genotype 2 or 3 HCV Infection Who Are Interferon Intolerant, Interferon Ineligible or Unwilling to Take Interferon (POSITRON), which enrolled GT 2/3 patients unable or unwilling to receive interferon, who were randomly assigned to receive 12 weeks of SOF+RBV or placebo; and Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection (FUSION), which enrolled treatment-experienced GT2/3 patients who received 12 or 16 weeks of SOF+RBV.

For all studies, the primary end point was sustained virologic response (HCV RNA < 25 IU/mL) at 12 weeks posttreatment (SVR12).

In the studies, participants had a mean age of 53 years (range, 19 - 77 years) and a mean body mass index of 28 kg/m2 (range, 17 - 56 kg/m2). Demographics were consistent with those of the HCV-infected population in the United States. Six percent of the participants were receiving opioid replacement therapy.

Table 1. 12-Week SVR Rates

  GT 1,4,5,6 GT 2 and 3
NEUTRINO FISSION POSITRON FUSION
SOF/PEG/RBV (n = 327) SOF/RBV (n = 253) PEG/RBV (n = 243) SOF/RBV (n = 207) Placebo (n = 71) SOF/RBV 12 week (n = 100) SOF/RBV 16 week (n = 95)
Overall 91% 67% 67% 78% 0% 50% 73%
GT 2 N/A 97% 78% 93% 0% 86% 94%
GT 3 N/A 56% 63% 61% 0% 30% 62%
Noncirrhotic 93% 72% 74% 81% 0% 61% 76%
Cirrhotic 80% 47% 38% 61% 0% 31% 66%

Compensated cirrhosis at baseline was found in 17% of patients in the NEUTRINO study, 21% in FISSION, 18% in POSITRON, and 33% in FUSION.

In all studies, SVR12 was higher in patients without cirrhosis. Patients with GT 2 experienced higher SVR12 rates than those with GT 3.

SVR 24 rates were similar to SVR 12 rates.

 

Table 2. SVR12 vs SVR24

  SVR12 SVR24
Treatment-naïve patients    
GT 1, 4, 5, 6 overall 91% 91%
GT 1 90% 90%
GT 4 96% 96%
GT 5 and GT 6 100% 100%
Treatment-naive and experienced GT 2, 3 patients    
Treatment-naive 67% 67%
Interferon unable 78% 78%
Previously treated (12 week regimen) 51% 50%
Previously treated (16 week regimen) 73% 72%

The additional data back up the 12-week SVR. "In all the studies, the 24-week results are almost identical [to the 12-week SVR]. We detected durability of that response," said Dr. Kowdley. The studies also suggest that interferon is not needed to achieve SVR in genotypes 2 and 3, although Dr. Kowdley said that trials of interferon-sparing regimens are underway.

The results further underscore the anticipation that physicians have toward sofosbuvir and other new drugs. "I think 2 years ago there was a standing-room only meeting in San Francisco, where Pharmasset (which originally developed sofosbuvir), dropped just unbelievable results, and we all thought this was too good to be true," Tim Little, MD, a physician with Puget Sound Gastroenterology in Seattle, Washington, who attended the presentation, told Medscape Medical News.

"I don't know that there's anything incredibly new about (this study), but it's confirmation that this dramatic result that this very small group of investigators presented is actually real, and I think we can all understand that this is as good as they said it was going to be, or almost as good," Dr. Little said.

On October 25, an FDA advisory committee unanimously recommended approval of sofosbuvir based on the 12-week results. The FDA is expected to make a decision by December 8.

The research was funded by Gilead Bioscences, which is sponsoring sofosbuvir. Dr. Kowdley has received research funding from Gilead and is a member of the company's advisory committee. Dr. Little has disclosed no relevant financial relationships.

American College of Gastroenterology (ACG) 2013 Annual Scientific Meeting and Postgraduate Course: Abstract 38. Presented October 15, 2013.

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Alcohol and Cancer Risk (Fact Sheet)

Provided by OncologyNurseAdvisor

October 28, 2013

What is alcohol?

Alcohol is the common term for ethanol or ethyl alcohol, a chemical substance found in beer, wine, and liquor, as well as in some medicines, mouthwashes, household products, and essential oils (scented liquids taken from plants). Alcohol is produced by the fermentation of sugars and starches by yeast.

The main types of alcoholic drinks and their alcohol content are as follows:

  • Beers and hard ciders: 3-7 percent alcohol
  • Wines, including sake: 9-15 percent alcohol
  • Wines fortified with liquors, such as port: 16-20 percent alcohol

Liquor, or distilled spirits, such as gin, rum, vodka, and whiskey, which are produced by distilling the alcohol from fermented grains, fruits, or vegetables: usually 35-40 percent alcohol (70-80 proof), but can be higher

According to the National Institute on Alcohol Abuse and Alcoholism, a standard alcoholic drink in the United States contains 14.0 grams (0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in

  • 12 ounces of beer
  • 8 ounces of malt liquor
  • 5 ounces of wine
  • 1.5 ounces or a "shot" of 80-proof liquor

The federal government's Dietary Guidelines for Americans 2010 defines moderate alcohol drinking as up to one drink per day for women and up to two drinks per day for men. Heavy alcohol drinking is defined as having more than three drinks on any day or more than seven drinks per week for women and more than four drinks on any day or more than 14 drinks per week for men.

What is the evidence that alcohol drinking is a cause of cancer?

Based on extensive reviews of research studies, there is a strong scientific consensus of an association between alcohol drinking and several types of cancer (1, 2). In its Report on Carcinogens, the National Toxicology Program of the US Department of Health and Human Services lists consumption of alcoholic beverages as a known human carcinogen. The research evidence indicates that the more alcohol a person drinks—particularly the more alcohol a person drinks regularly over time—the higher his or her risk of developing an alcohol-associated cancer. Based on data from 2009, an estimated 3.5 percent of all cancer deaths in the United States (about 19,500 deaths) were alcohol related (3).

Clear patterns have emerged between alcohol consumption and the development of the following types of cancer:

Head and neck cancer: Alcohol consumption is a major risk factor for certain head and neck cancers, particularly cancers of the oral cavity (excluding the lips), pharynx (throat), and larynx (voice box) (4). People who consume 50 or more grams of alcohol per day (approximately 3.5 or more drinks per day) have at least a two to three times greater risk of developing these cancers than nondrinkers (4). Moreover, the risks of these cancers are substantially higher among persons who consume this amount of alcohol and also use tobacco (5).

Esophageal cancer: Alcohol consumption is a major risk factor for a particular type of esophageal cancer called esophageal squamous cell carcinoma (2). In addition, people who inherit a deficiency in an enzyme that metabolizes alcohol have been found to have substantially increased risks of alcohol-related esophageal squamous cell carcinoma (see

Liver cancer: Alcohol consumption is an independent risk factor for, and a primary cause of, liver cancer (hepatocellular carcinoma) (6). (Chronic infection with hepatitis B virus and hepatitis C virus are the other major causes of liver cancer.)

Breast cancer: More than 100 epidemiologic studies have looked at the association between alcohol consumption and the risk of breast cancer in women. These studies have consistently found an increased risk of breast cancer associated with increasing alcohol intake. A meta-analysis of 53 of these studies (which included a total of 58,000 women with breast cancer) showed that women who drank more than 45 grams of alcohol per day (approximately three drinks) had 1.5 times the risk of developing breast cancer as nondrinkers (a modestly increased risk) (7). The risk of breast cancer was higher across all levels of alcohol intake: for every 10 grams of alcohol consumed per day (slightly less than one drink), researchers observed a small (7 percent) increase in the risk of breast cancer. 

The Million Women Study in the United Kingdom (which included more than 28,000 women with breast cancer) provided a more recent, and slightly higher, estimate of breast cancer risk at low to moderate levels of alcohol consumption: every 10 grams of alcohol consumed per day was associated with a 12 percent increase in the risk of breast cancer (8).

Colorectal cancer: Alcohol consumption is associated with a modestly increased risk of cancers of the colon and rectum. A meta-analysis of 57 cohort and case-control studies that examined the association between alcohol consumption and colorectal cancer risk showed that people who regularly drank 50 or more grams of alcohol per day (approximately 3.5 drinks) had 1.5 times the risk of developing colorectal cancer as nondrinkers or occasional drinkers (9). For every 10 grams of alcohol consumed per day, there was a small (7 percent) increase in the risk of colorectal cancer.

Research on alcohol consumption and other cancers:

Numerous studies have examined the association between alcohol consumption and the risk of other cancers, including cancers of the pancreas, ovary, prostate, stomach, uterus, and bladder. For these cancers, either no association with alcohol use has been found or the evidence for an association is inconsistent. 

However, for two cancers—renal cell (kidney) cancer and non-Hodgkin lymphoma (NHL)—multiple studies have shown that increased alcohol consumption is associated with a decreased risk of cancer (10, 11). A meta-analysis of the NHL studies (which included 18,759 people with NHL) found a 15 percent lower risk of NHL among alcohol drinkers compared with nondrinkers (11). The mechanisms by which alcohol consumption would decrease the risks of either renal cell cancer or NHL are not understood.

How does alcohol increase the risk of cancer?

Researchers have identified multiple ways that alcohol may increase the risk of cancer, including:

  • ametabolizing (breaking down) ethanol in alcoholic drinks to acetaldehyde, which is a toxic chemical and a probable human carcinogen; acetaldehyde can damage both DNA (the genetic material that makes up genes) and proteins (see Question 5)
  • generating reactive oxygen species (chemically reactive molecules that contain oxygen), which can damage DNA, proteins, and lipids (fats) through a process called oxidation
  • impairing the body's ability to break down and absorb a variety of nutrients that may be associated with cancer risk, including vitamin A; nutrients in the vitamin B complex, such as folate; vitamin C; vitamin D; vitamin E; and carotenoids
  • increasing blood levels of estrogen, a sex hormone linked to the risk of breast cancer

Alcoholic beverages may also contain a variety of carcinogenic contaminants that are introduced during fermentation and production, such as nitrosamines, asbestos fibers, phenols, and hydrocarbons.

How does the combination of alcohol and tobacco affect cancer risk?

Epidemiologic research shows that people who use both alcohol and tobacco have much greater risks of developing cancers of the oral cavity, pharynx (throat), larynx, and esophagus than people who use either alcohol or tobacco alone. In fact, for oral and pharyngeal cancers, the risks associated with using both alcohol and tobacco are multiplicative; that is, they are greater than would be expected from adding the individual risks associated with alcohol and tobacco together (5, 12).

Can a person's genes affect their risk of alcohol-related cancers?

A person's risk of alcohol-related cancers is influenced by their genes, specifically the genes that encode enzymes involved in metabolizing (breaking down) alcohol (13).

For example, one way the body metabolizes alcohol is through the activity of an enzyme called alcohol dehydrogenase, or ADH. Many individuals of Chinese, Korean, and especially Japanese descent carry a version of the gene for ADH that codes for a "superactive" form of the enzyme. This superactive ADH enzyme speeds the conversion of alcohol (ethanol) to toxic acetaldehyde. As a result, when people who have the superactive enzyme drink alcohol, acetaldehyde builds up. Among people of Japanese descent, those who have this superactive ADH have a higher risk of pancreatic cancer than those with the more common form of ADH (14).

Another enzyme, called aldehyde dehydrogenase 2 (ALDH2), metabolizes toxic acetaldehyde to non-toxic substances. Some people, particularly those of East Asian descent, carry a variant of the gene for ALDH2 that codes for a defective form of the enzyme. In people who have the defective enzyme, acetaldehyde builds up when they drink alcohol. The accumulation of acetaldehyde has such unpleasant effects (including facial flushing and heart palpitations) that most people who have inherited the ALDH2 variant are unable to consume large amounts of alcohol. Therefore, most people with the defective form of ALDH2 have a low risk of developing alcohol-related cancers.

However, some individuals with the defective form of ALDH2 can become tolerant to the unpleasant effects of acetaldehyde and consume large amounts of alcohol. Epidemiologic studies have shown that such individuals have a higher risk of alcohol-related esophageal cancer, as well as of head and neck cancers, than individuals with the fully active enzyme who drink comparable amounts of alcohol (15). These increased risks are seen only among people who carry the ALDH2 variant and drink alcohol—they are not observed in people who carry the variant but do not drink alcohol.

Can drinking red wine help prevent cancer?

Researchers conducting studies using purified proteins, human cells, and laboratory animals have found that certain substances in red wine, such as resveratrol, have anticancer properties (16). Grapes, raspberries, peanuts, and some other plants also contain resveratrol. However, clinical trials in humans have not provided evidence that resveratrol is effective in preventing or treating cancer (17). Few epidemiologic studies have looked specifically at the association between red wine consumption and cancer risk in humans. 

What happens to cancer risk after a person stops drinking alcohol?

Most of the studies that have examined whether cancer risk declines after a person stops drinking alcohol have focused on head and neck cancers and on esophageal cancer. In general, these studies have found that stopping alcohol consumption is not associated with immediate reductions in cancer risk; instead, it may take years for the risks of cancer to return to those of never drinkers.

For example, a pooled analysis of 13 case-control studies of cancer of the oral cavity and pharynx combined found that alcohol-associated cancer risk did not begin to decrease until at least 10 years after stopping alcohol drinking. Even 16 years after they stopped drinking alcohol, the risk of cancer was still higher for ex-drinkers than for never drinkers (18).

In several studies, the risk of esophageal cancer was also found to decrease slowly with increasing time since stopping alcohol drinking. A pooled analysis of five case–control studies found that the risk of esophageal cancer did not approach that of never drinkers for at least 15 years after stopping alcohol drinking (18).

Is it safe for someone to drink alcohol while undergoing cancer chemotherapy?

As with most questions related to a specific individual's cancer treatment, it is best for a patient to check with their health care team about whether or not it is safe to drink alcohol during or immediately following chemotherapy treatment. The doctors and nurses administering the treatment will be able to give specific advice about whether drinking alcohol is safe with particular chemotherapy drugs and/or other medications prescribed along with chemotherapy.

Selected References

1. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Alcohol consumption and ethyl carbamate Exit Disclaimer. IARC Monographs on the Evaluation of Carcinogenic Risks in Humans 2010;96:3-1383.

2. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Personal habits and indoor combustions. Volume 100 E. A review of human carcinogens. Exit Disclaimer IARC Monographs on the Evaluation of Carcinogenic Risks in Humans 2012;100(Pt E):373-472.

3. Nelson DE, Jarman DW, Rehm J, et al. Alcohol-attributable cancer deaths and years of potential life lost in the United States. American Journal of Public Health 2013;103(4):641-648.

4. Baan R, Straif K, Grosse Y, et al. Carcinogenicity of alcoholic beverages Exit Disclaimer. Lancet Oncology 2007;8(4):292-293.

5. Hashibe M, Brennan P, Chuang SC, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiology, Biomarkers & Prevention 2009;18(2):541-550.

6. Grewal P, Viswanathen VA. Liver cancer and alcohol. Clinics in Liver Disease 2012;16(4):839-850.

7. Hamajima N, Hirose K, Tajima K, et al. Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. British Journal of Cancer 2002;87(11):1234-1245.

8. Allen NE, Beral V, Casabonne D, et al. Moderate alcohol intake and cancer incidence in women. Journal of the National Cancer Institute 2009;101(5):296-305.

9. Fedirko V, Tramacere I, Bagnardi V, et al. Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Annals of Oncology 2011;22(9):1958-1972.

10. Bellocco R, Pasquali E, Rota M, et al. Alcohol drinking and risk of renal cell carcinoma: results of a meta-analysis. Annals of Oncology 2012;23(9):2235-2244.

11. Tramacere I, Pelucchi C, Bonifazi M, et al. A meta-analysis on alcohol drinking and the risk of Hodgkin lymphoma. European Journal of Cancer Prevention 2012;21(3):268-273.

12. Turati F, Garavello W, Tramacere I, et al. A meta-analysis of alcohol drinking and oral and pharyngeal cancers: results from subgroup analyses. Alcohol and Alcoholism 2013;48(1):107-118.

13. Druesne-Pecollo N, Tehard B, Mallet Y, et al. Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer. Lancet Oncology 2009;10(2):173-180.

14. Kanda J, Matsuo K, Suzuki T, et al. Impact of alcohol consumption with polymorphisms in alcohol-metabolizing enzymes on pancreatic cancer risk in Japanese. Cancer Science 2009;100(2):296-302.

15. Yokoyama A, Omori T. Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers Exit Disclaimer. Alcohol 2005;35(3):175-185.

16. Athar M, Back JH, Tang X, et al. Resveratrol: a review of preclinical studies for human cancer prevention. Toxicology and Applied Pharmacology 2007;224(3):274-283.

17. Patel KR, Scott E, Brown VA, et al. Clinical trials of resveratrol. Annals of the New York Academy of Sciences 2011;1215:161-169.

18. Rehm J, Patra J, Popova S. Alcohol drinking cessation and its effect on esophageal and head and neck cancers: a pooled analysis. International Journal of Cancer 2007;121(5):1132-1137.

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JAMA study questions FDA's shorter drug approval times

By Toni Clarke

WASHINGTON | Tue Oct 29, 2013 3:53am IST

WASHINGTON (Reuters) - New drugs that receive expedited review by the Food and Drug Administration are being tested on fewer patients, leaving many safety questions unanswered even after they are approved, a study released on Monday in the Journal of the American Medical Association found.

Study authors Thomas Moore of the Institute for Safe Medication Practices and Dr Curt Furberg, a professor at Wake Forest School of Medicine, examined the development times, clinical testing and risks associated with 20 new drugs approved in 2008. Eight were given expedited review and 12 standard review.

It found that expedited drugs underwent a median of 5.1 years of clinical testing before being approved, compared with 7.5 years for those that underwent a standard review. But in many cases safety monitoring trials that were supposed to be conducted after the products were approved were either not conducted, not completed, or not submitted to the FDA.

"The testing of new drugs has shifted from a situation in which most testing was conducted prior to initial approval to a situation in which many innovative drugs are more rapidly approved after a small trial in a narrower patient population with extensive additional testing conducted after approval," the authors said.

At the urging of patient groups, Congress and the drug industry, the FDA over the past decade has introduced multiple mechanisms for speeding new products to the market. While patient groups and drug companies applaud these measures, saying they get much-needed medication into the hands of patients more quickly, critics say the agency is approving products before they have been fully vetted.

Of the drugs studied by Moore and Furberg in 2008, the FDA required 85 follow-up trials to monitor for safety. By 2013, only 40 percent of those studies had been completed.

The FDA said in a statement that it will review the article in more detail but that on the surface "it shows that the expedited development programs are working as intended by getting promising new drugs to patients more quickly."

RELAXED EVIDENCE

The FDA has traditionally required two controlled clinical trials to prove that a drug is safe and effective. Over time the agency has relaxed the evidence it is willing to accept for certain products.

In some cases the FDA will accept data from a single trial and success may be judged on the basis of a surrogate measure - such as tumor shrinkage - that may or may not translate into a concrete measure such as increased survival.

"In situations of serious and life-threatening diseases with unmet medical need, patients and physicians who treat them have told us repeatedly that they are willing to accept greater uncertainty about risk in order to have access to the hope of improved treatment today," the FDA said in its statement.

The FDA is discussing additional measures to speed the drug development process, including the use of "enriched" trials that would select patients based on certain demographic or genetic characteristics in order to increase the chance of a trial's success.

The idea is to direct treatment to patients for whom it will be most effective or who are most likely to respond.

But in a commentary published alongside the study, Daniel Carpenter, a professor of government at Harvard University, said the FDA has put few measures in place to ensure that drugs that are approved based on limited populations are only marketed to those limited groups.

"The current system of accelerating drug approval in the United States can be described as a growing hodgepodge of exceptions to the rule of rigorous premarket review," he said.

The FDA said it has a "robust program for postmarketing surveillance and ensuring the completion of required post-approval trials."

"We believe that we have set the bar for the balance between pre-approval testing and early availability of promising new drugs to treat serious and life-threatening diseases in the right place."

(Reporting by Toni Clarke in Washington; editing by Matthew Lewis)

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Provided by MedicalXpress

October 28, 2013

Infants who get hepatitis C from their mothers during childbirth may inherit a viral strain that replicates more quickly than strains found in non-pregnant hosts, according to a new study published Oct. 27 in Nature Medicine. The findings, from a team in The Research Institute at Nationwide Children's Hospital, are the first to describe how a virus that has infected 180 million people worldwide takes advantage of immune changes during pregnancy.

About 1 percent of all pregnant women worldwide have hepatitis C, caused by a highly adaptable virus known as HCV that infects liver cells. In 3 to 5 percent of these pregnancies, the virus is passed to the newborns, accounting for the majority of new childhood HCV infections. Between 15 and 45 percent of people infected with HCV are able to mount an immune response sufficient to eradicate the virus. But in most cases, the virus eludes immunity, leading to a chronic infection that increases the risk of liver failure or liver cancer.

As part of a larger study of HCV in pregnant women and infants, researchers at Nationwide Children's followed two women with hepatitis C over a five-year period. Both women had two children during this time, and researchers were able to track the virus before, during and after pregnancy. Their analysis revealed surprising changes in HCV genomes that not only allowed the virus to thrive, but also ensured that the strain passed on by one of the women during childbirth was particularly good at replication, says Jonathan R. Honegger, MD, an infectious disease specialist and principal investigator in the Center for Vaccines and Immunity at Nationwide Children's.

"We found that better replicating versions of the virus emerged during pregnancy, and these 'fit' viruses were passed to the babies." Dr. Honegger says. "The findings actually provide unique insight into the impact of pregnancy on the mothers' control of viral infections, and also a striking illustration of this virus' ability to adapt to changing environmental pressures."

HCV persists in the general population, in part, because the virus outwits the immune system with mutations that can render it undetectable to CD8+ T-cells, important weapons in the body's antiviral immune arsenal. Although these viral variations—called immune escape mutations—protect the virus from attack by T-cells, they sometimes slow the virus replication machinery.

During pregnancy, T-cells are restrained to prevent the body from attacking the fetus as foreign tissue. Viral levels of HCV have also been known to increase during pregnancy, but whether this was related to changes in T-cell function was unknown. Working closely with Chris Walker, director of the Center for Vaccines and Immunity, and colleagues at Emory University and the University of North Carolina, Dr. Honegger found that during pregnancy, certain T-cell escape mutations were lost, resulting in a virus that could replicate far more quickly.

"This surprised us because the virus' immune escape mutations are usually stable in a patient," Dr. Honegger says. "The loss of these immune escape mutations from HCV during pregnancy provided strong evidence that the immune changes of pregnancy, intended to protect the fetus, significantly impaired the ability of CD8+ T-cells to exert pressure on the virus."

Loss of the escape mutations also meant that the babies got a version of the virus that was optimized for viral replication, Dr. Honegger adds. In the children they studied, the virus persisted and did not mutate in a way to suggest that it was under significant attack by their CD8+ T-cells.

"We don't yet know whether getting the fast-replicating, immune-susceptible version of the virus would be an advantage for the baby or the virus," says Dr. Honegger, who also is an assistant professor of pediatrics at The Ohio State University. "We suspect that if the baby doesn't mount a swift and strong immune response, then fast viral replication may increase the risk of persistent infection in the baby."

On the other hand, viral loads in the mothers dropped more than 1,000 fold by 12 weeks after delivery and viral genetic analysis showed that immune escape mutations had returned. "We interpreted this to mean that T-cell activity against hepatitis C in the liver increased sharply after delivery," Dr. Honegger says.

Researchers now are following a larger group of pregnant women with HCV, hoping to learn more about how viral mutations affect the way the body controls hepatitis C in pregnant women and infants.

"We believe that better understanding of the natural history of the infection in these patients will be critical for designing rational strategies to treat or prevent HCV in these populations."

Explore further: Study examines ways to restore immunity to chronic hepatitis C infection

More information: Honegger JR, Kim S, Price AA, Kohout JA, McKnight KL, Prasad MR, Lemon SM, Grakoui A, Walker CM. Loss of Immune Escape Mutations During Persistent HCV Infection in Pregnancy Enhances Replication of Vertically Transmitted Viruses. Nature Medicine. 2013 Oct 27. DOI: 10.1038/nm.3351 [Epub ahead of print]

Journal reference: Nature Medicine

Provided by Nationwide Children's Hospital

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Why Gilead's Sofosbuvir Is Better Than J&J's Simeprevir

Provided by The Motley Fool

By Todd Campbell | More Articles
October 28, 2013

Johnson & Johnson's simeprevir Achilles' heel is Q80K. Coming out of the FDA's Antiviral Drugs Advisory Committee Meeting on Oct. 24, your takeaway should be that simeprevir is a very good drug with a smaller than hoped addressable market.

When data from J&J's two phase 3 trials were pooled together, patients with the Q80K polymorphism didn't benefit from simeprevir. The sustained viral response over 12 weeks, or SVR12, for Q80K patients was a statistically insignificant 58% versus 55% for the control arm.

"Most striking in the subgroup analysis was the substantial impact of the Q80K baseline HCV GT1a polymorphism on the efficacy of simeprevir. In subjects with the Q80K polymorphism at baseline, no statistically significant difference in SVR12 rates was observed when comparing the simeprevir group to the Control group," according to the advisory committee meeting materials.

Looking at the pooled non-Q80K patients, the SVR12 rate jumps to 84% for simeprevir patients versus just 43% for placebo. This means it's unlikely simprevir will get prescribed for patients with Q80K. That's unfortunate for J&J because Q80K was identified in 48% of HCV genotype 1a patients in J&J's phase 3 trials.

The high prevalence of Q80K in genotype 1 patients is important because in a U.S. study of HCV patients, 56.7% were classified as genotype 1a, 17% as 1b, 3.5% as 2a, 11.4% as 2b, 7.4% as 3a, 0.9% as 4, 3.2% as type 6.

"Given the high frequency of the Q80K polymorphism in the U.S. population and its significant impact on rates of SVR12, DAVP is recommending that all GT1a patients be screened for the Q80K polymorphism. Alternative treatment options should be considered for patients found to be infected with this polymorphic variant," the advisory committee materials went on to say.

The findings give Gilead's sofosbuvir an edge
That opens up an advantage for Gilead Sciences sofosbuvir, because sofosbuvir doesn't have the same reason for pause as simeprevir in Q80K patients. Sofosbuvir got the advisory panel's unanimous nod of recommendation two days after it recommended simeprevir.

But, Q80K isn't the only advantage sofosbuvir may have over J&J's simprevir. The holy grail of hepatitis C treatments remains discarding prior generation therapies peg-interferon and ribavirin, which are saddled with side effects.

While simprevir will be dosed as part of combination therapy including peg-interferon injections and ribavirin, the panel recommended sofosbuvir dosed with only ribavirin in HCV2 and HCV3 populations as part of an all-oral therapy. In Gilead's phase 3 POSITRON study of patients unwilling or unable to take interferon, SVR12 was 78% versus 0% for placebo.

That two-drug combination provided better outcomes and shorter treatment periods than any of the current standard treatments available. Importantly, the absence of peg-interferon injections marks a big step forward in removing significant hurdles faced by patients who are either unwilling, or unable to tolerate interferon.

Those with the more common HCV1 and HCV4 genotypes will still need to be dosed with peg interferon, but treatment duration drops to 12 weeks, helping limit some of the side effects compared to existing treatment protocols. However, that leaves Gilead on equal footing with J&J in those patients.

You should also know that across Gilead's trials, 12-week dosing didn't have nearly as robust a rate of success in patients with genotype 3 as those with genotype 2. However, in Gilead's FUSION phase 3 trial, extending treatment to 16 weeks produced a much better outcome. In FUSION, the SVR jumped to 62% at week 16 from 38% at week 12. As a result, it's likely protocol for HCV3 patients treated with sofosbuvir will be for the longer treatment period.

The Foolish final take
The market for hepatitis C is big. The World Health Organization estimates around 170 million are infected worldwide with 2.7 million chronic cases in the U.S. Roughly 20,000 to 30,000 new cases are diagnosed in the U.S. each year.

Both drugs will likely win approval by the FDA, given its common to follow the advice of the advisory panels. But, sofosbuvir likely stands to benefit more than simeprivir when commercialized. However, it's not all bad for J&J.

In a phase 2a study called COSMOS, treating HCV1 patients who had previously failed on peg-interferon and ribavirin therapy with a combination of simeprivir and sofosbuvir without interferon or ribavirin, showed promising results, with SVR8 of 93%. That suggests while simeprevir isn't likely to win the script battle head to head with sofosbuvir, it may find itself part of a later combination therapy with the drug.

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Hepatitis C to Take Center Stage at the Liver Meeting

Medscape Medical News > Conference News

Miriam E. Tucker

October 28, 2013

With its major focus on hepatitis C screening and treatment, perhaps it's fitting that the Liver Meeting 2013 is taking place in Washington, DC, for the very first time, where just last week an advisory panel to the US Food and Drug Administration (FDA) voted in favor of licensing 2 direct-acting antiviral agents — sofosbuvir and simeprevir — that represent major advances in hepatitis C treatment.

"We're excited about it," American Association for the Study of Liver Diseases (AASLD) president J. Gregory Fitz, MD, told Medscape Medical News. "This is the 64th meeting of the organization, and the first time in Washington. So far, the attendance looks like it's going to set new records."

The projected attendance, some 10,000 liver specialists from more than 50 different countries, "reflects the excitement in the field," said Dr. Fitz, "but also the needs in the field and the searching for answers."

This summer, the US Preventive Services Task Force for the first time recommended hepatitis C screening for all baby boomers.

The Liver Meeting's scientific program committee chair Gary Davis, MD, said, "I think most people at both this meeting and the European meeting are most fascinated by what's happening with hepatitis C because that's an area that is changing so fast right now."

With the FDA's antiviral drugs advisory committee's endorsement of the NS5B polymerase inhibitor sofosbuvir, hepatologists are now excitedly looking toward a new era of all-oral, interferon-free regimens that are expected to successfully treat a greater proportion of infected patients with lower toxicity.

Dr. Davis told Medscape Medical News that the abstracts at the meeting will pick up where the data submitted to the FDA left off, with studies looking at more potential uses for sofosbuvir and other direct-acting antiviral agents in various drug combinations. "Some of the abstracts that are being presented are giving us a peek at what the next incremental steps are likely to be, and those are coming soon," he said.

Still, not everything at the conference will be about hepatitis C. Other hot topics include nonalcoholic fatty liver disease, which is an outgrowth of the obesity epidemic, prevention of acute-on-chronic liver failure in cirrhosis patients, drug-induced hepatotoxicity, and the recent rise in the incidence of liver cancer at a time when other cancer rates in the United States are declining.

In all, Dr. Fitz told Medscape Medical News, liver disease is now the eighth leading cause of death in the United States. "Despite huge progress in the field, the burden of diseases continues to increase."

Attendees looking for a broad overview of the very latest trends in their specialty can attend the AASLD Postgraduate Course on New Treatments in Liver Disease. The course, which will be held on Friday afternoon, will cover new diagnostic approaches, including genetic testing, noninvasive alternatives to biopsy, and new biomarkers for hepatocellular carcinoma.

State-of-the-Art Hepatology

A Friday evening course, entitled Old Diseases, New Treatments, will revisit conditions such as primary sclerosing cholangitis and iron overload. The course will devote entire sessions on Saturday morning to current and future management of viral hepatitis and fatty liver disease.

Previous meetings have featured the postgraduate course, but this year's will be particularly clinical, Dr. Davis, the former director of liver diseases at Baylor University Medical Center in Dallas, told Medscape Medical News.

"It will address a lot of questions and will reference many of the abstracts. In many areas, like hepatitis C, it's about incremental changes."

State-of-the-art lectures, from Sunday through Tuesday, will feature cutting-edge topics such as regenerative medicine, alpha-1 antitrypsin deficiency (a novel treatment strategy 50 years after discovery), acetaminophen and the liver, and hepatitis C therapeutics in the postinterferon era.

"I think the state of the arts this year are really great," Dr. Davis said, noting that he's particularly excited about the regenerative medicine talk Sunday morning by Anthony Atala, MD, director of the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina, who will discuss building organs from stem cells. "It will be a fascinating talk."

Both Dr. Davis and Dr. Fitz told Medscape Medical News they're looking forward to the president's choice lecture by Bruce Beutler, MD, winner of the Nobel Prize in physiology or medicine. Dr. Beutler, from the University of Texas Southwestern in Dallas, shared the Nobel for discoveries concerning the activation of innate immunity.

Dr. Fitz pointed out that Dr. Beutler's work relates to "pathways that are fundamental to almost all causes of liver diseases, so the lecture will be of interest to both the scientists and clinicians."

Extracurriculars

Younger faces are expected at this year's meeting because the society has made an effort to bring in more trainees, Dr. Fitz told Medscape Medical News.

"We've gone out very specifically to try to identify younger physicians and scientists who are interested in the liver and bring them to the meeting and get them engaged and show them what the future might look like. I'm looking forward to having everyone interact with these younger people and hearing their thoughts."

Dr. Fitz said that free time will be an important facet of the meeting to encourage such exchanges. "That's really important to the success of the meeting — to have the unstructured time for the right kind of interactions necessary for collaborations and future plans."

Many of those social interactions are likely to take place at the Saturday evening cocktail reception, where alcohol will be served. "Even liver doctors drink wine," he said. "Alcohol continues to be a very important cause of liver disease around the world, but all things in moderation. AASLD definitely has an antiexcess alcohol stance, but we're not going back to the prohibition era."

Dr. Fitz has disclosed no relevant financial relationships. Dr. Davis serves on data safety and monitoring boards for the Duke Research Institute and for Bristol-Myers Squibb for a nonhepatology drug.

Source

Novel antiviral for chronic hepatitis C backed for approval

By: ELIZABETH MECHCATIE, Family Practice News Digital Network

10/28/13

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has unanimously recommended the approval of sofosbuvir, a new antiviral drug, for treating adults with chronic hepatitis C infection, with several panelists describing the votes to approve the drug as historic.

At a meeting on Oct. 25, the FDA’s Antiviral Drugs Advisory Committee voted 15-0 to recommend approval of sofosbuvir for the treatment of two different chronic hepatitis C indications: In combination with pegylated interferon and ribavirin for treatment-naive adults with genotype 1 and 4 infections; and in combination with ribavirin for adults with genotype 2 and 3 infections.

If approved – which is expected – the second indication will mark the first approval of a treatment for chronic hepatitis C with an interferon-free regimen, and it will be the first drug in its class to be approved. Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B polymerase enzyme, which plays an important role in HCV replication and is active against HCV genotypes 1 (the most common genotype in the United States), 2, 3, 4, 5, and 6. It is taken orally once a day at a 400-mg dose.

This is "truly a historic moment," said panelist Dr. Demetre Daskalakis, medical director of the HIV program at Mt. Sinai School of Medicine, New York. "I can’t wait to get this drug into the clinic. We are all excited," he added. The consumer representative on the panel, Daniel Raymond, policy director at the Harm Reduction Coalition, New York City, said that the company had "pulled off the hat trick" of superior efficacy, safety, and convenience over current treatments.

"I voted yes because, quite simply, this is a game changer," said Dr. Marc Ghany, staff physician in the liver diseases branch at the National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md.

The manufacturer, Gilead Sciences, has proposed that sofosbuvir be approved for treating chronic hepatitis C infection in combination with other agents in adults with genotypes 1-6 and/or adults waiting for a liver transplant, with different regimens of ribavirin, with or without pegylated interferon. The data on patients with genotypes 5 and 6 and on pretransplant patients are limited, and the panel was not asked to vote on approval for patients with those genotypes, or on approval for the pretransplant population.

The company presented the results of four phase III trials in patients with genotypes 2 and 3, which included an open-label study and randomized double-blind studies. The primary endpoint in all studies was the sustained virologic response rate (undetectable HCV) 12 weeks after active treatment was stopped (SVR12). In the studies, more than 1,000 patients received sofosbuvir.

The SVR12 rates of genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks ranged from 93% to 97% among those who were treatment naive, and from 82% to 90% among those who were treatment experienced. For those with genotype 3 treated with sofosbuvir plus ribavirin for 24 weeks, the SVR12 rates were 93% among those who were treatment naive and 77% for those who were treatment experienced.

In an open-label study of 327 treatment-naive patients with genotypes 1, 4, 5, and 6, patients were treated with sofosbuvir plus pegylated interferon and ribavirin (PR) for 12 weeks. Most (292) of the patients had genotype 1, followed by genotype 4 (28 patients). The SVR12 rates were 89% among those with genotype 1 and 96% among those with genotype 4. The one patient with genotype 5 and all 6 patients with genotype 6 achieved an SVR12.

Gilead is also conducting a phase II study of patients on a liver transplant list who have hepatocellular carcinoma and genotypes 1-6 and were treated with sofosbuvir plus ribavirin for a maximum of 24 weeks (which was extended to 48 weeks) or until transplant. HCV almost always recurs after liver transplantation, and there are no approved treatments to prevent recurrence of HCV after liver transplantation. In the study, 64% of the patients met the primary efficacy endpoint – HCV RNA below detectable levels 12 weeks after transplant.

Panelists said there is a need to treat this group of patients, who are increasing in numbers and are very challenging to treat, and they should be studied further.

Summarizing the FDA’s view of the sofosbuvir data, Dr. Poonan Mishra, a medical officer in the FDA’s division of antiviral products, said that, for patients with chronic hepatitis C infection, sofosbuvir, in combination with ribavirin, provides the first "all oral interferon-free regimen" for patients with genotype 2 or 3 infections. Combined with pegylated interferon and ribavirin, sofosbuvir "provides improved efficacy and shorter treatment duration for patients with genotype 1 or 4 HCV infection," she added. The results in the liver transplant population were "encouraging," and address an unmet need for these patients, she said.

The regimens of sofosbuvir combined with ribavirin or PR in the study were well tolerated in the different groups of patients, including those waiting for liver transplant, and there were no clusters or trends of any specific types of adverse events identified. An evaluation of cardiac disorders in treated patients found no obvious safety issues related to cardiac toxicity, according to the FDA. A drug in development in the same class was associated with cardiac toxicity.

The FDA is expected to make a decision by Dec. 8. Sofosbuvir also is under review in the European Union, Australia, Canada, New Zealand, Switzerland and Turkey, according to Gilead.

The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

emechcatie@frontlinemedcom.com

Source

HIV drugs may get new role in fighting cancer

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By Ben Hirschler

Fri Oct 25, 2013 3:07pm EDT

(Reuters) - A type of HIV medicine that stops the AIDS virus from entering immune system cells could in future be put to work against cancer in new combination therapies being developed by drug companies.

Interest in using so-called CCR5 inhibitors to fight tumors was fuelled last year when U.S. researchers, testing the drugs on mice, reported a marked reduction in aggressive breast cancer cells spreading to the animals' lungs.

Researchers from the Thomas Jefferson University Kimmel Cancer Center described the results as "dramatic" after they were published in the Journal of Cancer Research.

Now industry analysts at Citi believe Merck & Co Inc is set to take things to the next stage by testing its CCR5 drug vicriviroc in cancer patients. The product was abandoned as a treatment for HIV in 2010 following an unsuccessful study.

Pfizer Inc and Bristol-Myers Squibb - which also have similar drugs in their portfolios - could follow suit, Citi said in a note on Friday.

Asked to comment on the suggestion that it would start testing vicriviroc in patients in 2014 as part of a combination therapy for cancer, a spokesman for Merck said: "We have not disclosed any such plans."

Citi said it expected vicriviroc to re-enter clinical testing in combination with cancer immunotherapy as Merck explores its potential across multiple tumor types, including melanoma, colorectal, breast, prostate and liver cancer.

Immunotherapy, which harnesses the body's immune system to fight cancer, is a hot new area for cancer research, with some experts predicting the approach will in future form the backbone of many cancer treatments.

However, drug combinations are expected to be critical to its success as oncologists will need to block cancer cells on several fronts at once.

One option is to combine two immunotherapies, while another approach, also being pursued by other companies like Roche Holding AG and AstraZeneca Plc, is to combine immunotherapy medicines with different drug types.

CCR5 inhibitors are one such option, given the encouraging signals from pre-clinical research. As these drugs have already been studied in HIV, their development could be relatively rapid.

Pfizer could also start clinical trials in cancer with its approved CCR5 drug Selzentry, which is currently marketed for HIV via the ViiV Healthcare alliance with GlaxoSmithKline Plc and Shionogi & Co Ltd.

Bristol, meanwhile, has a dual CCR2/5 inhibitor in mid-stage Phase II development, which is being tested for diabetes and kidney disease.

(Editing by Patrick Lannin)

Source

FDA panel endorses Gilead, Janssen hep. C drugs

October 28, 2013

Gilead said on Friday that an advisory committee unanimously recommended approval of an all-oral regimen containing its hepatitis C drug sofosbuvir and ribavirin in patients with genotypes 2 and 3. Those genotypes account for the minority of patients with hep. C in the US.

The FDA panel also voted 15-0 in support of approving sofosbuvir for use with pegylated interferon and ribavirin in treatment-naïve patients with the more prevalent type, genotype 1, as well as in genotype 4.

According to ISI Group analyst Mark Schoenebaum, panelists also  voiced support for use of the regimen in treatment-experienced patients with genotype 1.

Sofosbuvir, submitted to FDA April 8, was given priority review and Breakthrough Therapy designation. A final decision is expected Dec. 8. The agency doesn't have to follow the advice of its advisory panels, but often does.

Because it's likely to be the first and likely go-to therapy among a coming wave of all-oral HCV regimens, the once-daily nucleotide analogue has been forecast to achieve sales of between $4 billion and $7 billion a year.

Sofosbuvir's recommendation came a day after an advisory panel unanimously endorsed a protease inhibitor from Janssen, simeprivir, for use with pegylated interferon and ribavirin for the treatment of genotype 1 chronic HCV patients.

Source

J Hepatol. 2013 Nov;59(5):957-63. doi: 10.1016/j.jhep.2013.07.004. Epub 2013 Jul 10.

Han H, Noureddin M, Witthaus M, Park YJ, Hoofnagle JH, Liang TJ, Rotman Y.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.

Abstract

BACKGROUND & AIMS: Interferon treatment for chronic hepatitis C is associated with non-specific symptoms including fever. We aimed to determine the association of temperature changes with interferon antiviral activity.

METHODS: 60 treatment-naïve patients with chronic hepatitis C (67% genotype 1/4/6, 33% genotype 2/3) were admitted to start peginterferon alfa-2a and ribavirin in a clinical trial. Temperature was measured at baseline and 3 times daily for the first 24h and the maximal increase from baseline during that time (ΔTmax) was determined. Serum HCV-RNA, interferon-gamma-inducible protein-10 (IP-10) and expression of interferon-stimulated genes (ISGs - CD274, ISG15, RSAD2, IRF7, CXCL10) in peripheral blood mononuclear cells (PBMCs) were measured at very early time points, and response kinetics calculated. The IL28B single nucleotide polymorphism, rs12979860, was genotyped.

RESULTS: Temperatures rose by 1.2±0.8°C, peaking after 12.5h. ΔTmax was strongly associated with 1st phase virological decline (r=0.59, p<0.0001) and was independent of gender, cirrhosis, viral genotype or baseline HCV-RNA. The association with 1st phase decline was seen in patients with rs12989760CC genotype (r=0.65, p<0.0001) but not in CC/CT (r=0.13, p=0.53) and patients with CC genotype had a higher ΔTmax (1.4±0.8°C vs. 0.8±0.6°C, p=0.001). ΔTmax was associated with 6- and 24-h induction of serum IP-10 and of PBMC ISG expression, but only in patients with rs12989760CC. ΔTmax weakly predicted early virological response (AUC=0.68, CI 0.49-0.88).

CONCLUSIONS: Temperature rise following peginterferon injection is closely associated with virological response and is modulated by IL28B polymorphism, reflecting host interferon-responsiveness.

Published by Elsevier B.V.

KEYWORDS: EVR, Fever, HCV, Hepatitis C, IFN, IL28B, IP-10, ISG, Interferon alfa, PGE2, PegIFN, RVR, SVR, Temperature, Treatment, early virological response, hepatitis C virus, interferon, interferon-gamma-inducible protein-10, interferon-stimulated gene, peginterferon alfa 2a, prostaglandin E2, rapid virological response, sustained virological response

PMID: 23850879 [PubMed - in process]

Source

World J Gastroenterol. 2013 Oct 21;19(39):6665-78. doi: 10.3748/wjg.v19.i39.6665.

Ye XG, Su QM.

Xiao-Guang Ye, Qi-Min Su, Department of Infectious Diseases, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China.

Abstract

AIM: To compare the effects of entecavir (ETV) and lamivudine (LAM) for the treatment of hepatitis B decompensated cirrhosis using a meta-analysis.

METHODS: We conducted a literature search for all eligible studies published prior to May 30, 2013 using PUBMED, MEDLINE, EMBASE, the China National Knowledge Infrastructure (CNKI), the VIP database, the Wanfang database and the Cochrane Controlled Trial Register. Randomized controlled trials (RCTs) comparing ETV with LAM for the treatment of hepatitis B decompensated cirrhosis were included. The data were analyzed with Review Manager Software 5.0.2. We used RR as an effect measure, and reported its 95%CI. The meta-analysis was performed using either a fixed-effect or random-effect model, based on the absence or presence of significant heterogeneity. Two reviewers assessed the risk of bias and extracted data independently and in duplicate. The analysis was executed using the main outcome parameters including hepatitis B virus (HBV) DNA undetectability, HBV DNA level, hepatitis B e antigen (HBeAg) seroconversion, alanine aminotransferase (ALT) level, albumin level, total bilirubin (TBIL) level, prothrombin time activity (PTA) level, Child-Turcotte-Pugh (CTP) score, mortality, drug-resistance, and adverse reactions. Meta-analysis of the included trials and subgroup analyses were conducted to examine the association between pre-specified characteristics and the therapeutic effects of the two agents.

RESULTS: Thirteen eligible trials (873 patients in total) were included and evaluated for methodological quality and heterogeneity. Of these studies, all had baseline comparability, 12 of them reported baseline values of the two treatment groups in detail. Following various treatment durations (12, 24, 36, 48 and > 48 wk), both ETV and LAM significantly reduced HBV DNA level, however, reductions were greater in the ETV group (MD = -0.66, 95%CI: -0.83-0.50, P < 0.00001), (MD = -0.93, 95%CI: -1.36-0.51, P < 0.0001), (MD = -1.4, 95%CI: -1.78-1.01, P < 0.00001), (MD = -1.18, 95%CI: -1.90-0.46, P = 0.001), (MD = -0.14, 95%CI: -0.17-0.11, P < 0.00001, respectively). At 12, 24 and 48 wk of treatment, ETV had a significant effect on the rate of HBV DNA undetectability (RR = 1.55, 95%CI: 1.22-1.99, P = 0.0004), (RR = 1.25, 95%CI: 1.13-1.38, P < 0.0001), (RR = 1.2, 95%CI: 1.10-1.32, P < 0.0001, respectively). Although HBeAg seroconversion in the ETV group was more pronounced than that in the LAM group at 24 wk (27.90% vs 26.19%) and 48 wk (31.52% vs 25.00%) of treatment, there was no statistically significant difference between them (RR = 1.49, 95%CI: 0.98-2.28, P = 0.07), (RR = 1.27, 95%CI: 0.98-1.65, P = 0.07, respectively). Following various treatment durations, both the ETV group and the LAM group showed significantly improved liver function (ALT, AIB, TBIL, PTA and CTP levels) and reduced mortality (ETV 6.37%, LAM 7.89%). The effects in the ETV group (0.33%) were statistically lower than those in the LAM group (14.33%) regarding the rate of drug-resistance (RR = 0.1, 95%CI: 0.04-0.24, P ≤ 0.00001). In addition, no severe adverse reactions were observed in the two treatment groups.

CONCLUSION: ETV and LAM significantly improved liver function and reduced mortality. Both drugs produced similar serological responses, and were safe and well tolerated. However, ETV resulted in a better virological response and lower drug-resistance, but is more expensive.

KEYWORDS: Decompensated cirrhosis, Entecavir, Hepatitis B, Lamivudine, Meta-analysis., Randomized controlled trial

PMID: 24151397 [PubMed - in process] Free PMC Article

Source

J Korean Med Sci. 2013 October; 28(10): 1449–1453.

Published online 2013 September 25. doi:  10.3346/jkms.2013.28.10.1449

PMCID: PMC3792598

Changhyun Lee, Jong In Yang, Hee Jin Byun, Jung Mook Kang, Seoungho Choi, and Jeong Yoon Yim

Abstract

This study aimed to investigate the status of primary liver cancers found through a routine health check-up. The data of subjects who were diagnosed with primary liver cancer for the first time through a routine health check-up during a period of 8-yr were analyzed. Primary liver cancers were detected for the first time in 34 subjects among 91,219 routine health check-up subjects. Only 11.8% of primary liver cancer subjects had been under previous surveillance. Of them, 55.8% were positive for HBsAg, 17.7% were positive for anti-HCV, and 8.8% were heavy alcohol comsumers. However, 17.7% of the subjects were neither heavy alcohol consumers nor positive for both HBsAg and anti-HCV. Of the subjects, 50.0% had a single nodular tumor, 23.5% had multi-nodular tumors, and 26.5% had an infiltrative tumor. A routine health check-up may provide beneficial opportunities to detect a liver cancer in a very early stage. It is beneficial to start surveillance in high-risk subjects for liver cancer or to detect any liver cancer in subjects without risk factors of chronic viral hepatitis or heavy alcohol consumption.

Keywords: Liver Neoplasms, Mass Screening, Population Surveillance

INTRODUCTION

According to many guidelines, surveillance for liver cancer is strongly recommended in high risk subjects to improve prognosis by early diagnosis (1-4). Hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection and heavy alcohol consumption are representative risk factors for liver cancer (3). As Korea has been an endemic area of HBV, liver cancer also has been a major public health problem in Korea (5). Actually in 2011, liver cancer was ranked as the second most common cause of cancer mortality in Korea (6). Therefore, surveillance for liver cancer in high-risk subjects for liver cancer may be important in view of improving not only personal health but also public health in Korea (5, 7). Since 2001, in order to reduce the clinical burden of liver cancer through early diagnosis and treatment, the Ministry of Health and Welfare, Republic of Korea Government has recommended the regular surveillance of subjects older than 40 yr who are at a high risk for liver cancer (8).

Routine health check-ups are performed on people in Korea for the purpose of primary prevention or secondary prevention of major public health problems such as cancers or cardiovascular disease. Therefore, a routine health check-up may be a good chance not only to perform essential surveillance activities but also to detect liver cancer in the early stage. The purpose of this study was to study the characteristics of liver cancers found during routine health check-ups and their previous surveillance status in one health check-up specialized center which exists as a part of a major tertiary hospital in Korea.

MATERIALS AND METHODS

Study subjects

A total of 91,219 subjects (48,122 males and 43,097 females) received a routine health check-up which included abdominal ultrasonography (USG) or computed tomography (CT) at the Seoul National University Hospital Healthcare System Gangnam Center (Seoul, Korea) between October, 2003 and August, 2011. Among these 91,219 subjects, those who were diagnosed with liver cancer were extracted for this study. After excluding the 17 subjects with a previous history of liver cancer, the subjects who were diagnosed with liver cancer for the first time during a routine health check-up or during a surveillance which had started after a routine health check-up were the final subjects for this study.

Methods

Each subject answered a questionnaire, underwent anthropometric assessment, and had laboratory tests and a radiologic study of abdominal USG or CT done on the same health check-up day. Data about age, gender, cigarette smoking, amount of alcohol intake, family history of cancer, and general symptoms about weakness, weight loss or dyspepsia were collected from the questionnaire. Body mass index (BMI) was calculated by dividing the weight in kilograms by square of the height in meters. Laboratory tests included serum hepatitis B surface antigen (HBsAg), an antibody to hepatitis C virus (anti-HCV) and alpha-fetoprotein (αFP). Blood samples were collected from each subject before 10 a.m. after an overnight fast. All biochemical analyses of blood samples were performed in the same quality-controlled laboratory and done according to standard laboratory methods. Abdominal magnetic resonance imaging (MRI) or USG guided liver biopsy were performed on a separate day if needed diagnostically. A heavy alcohol consumer was defined as a person who consumed more than 80 g of alcohol per drinking session and drank more than 5 times a week for more than 10 yr (9). All USG, CT and MRI were assessed by radiologists. Liver cirrhosis was assessed by surface nodularities of a liver, regenerating nodules in a liver and/or an accompained hypersplenism. Liver cancer was diagnosed according to the Practice Guidelines for Management of Hepatocellular Carcinoma (2009) (10). Nodular tumor was divided into single nodular or multinodular type by the number of tumor nodules. Infiltrative tumor was diagnosed if more than 50% of a tumor margin showed infiltrative and irregular invasion into adjacent liver tissues. Primary liver cancer found during a routine health check-up was treated by surgery, percutaneous ethanol injection, radiofrequency ablation or transarterial chemoembolization at the main tertiary Seoul National University Hospital (11-13).

Statistical analysis

The data were expressed as the mean ± standard deviation. However, for data which did not follow standard normal distribution, data were expressed as median and range. Intergroup differences in continuous variables were explored by using Kruskal-Wallis test or Student's t-test. Intergroup differences in frequency variables were explored by chi-square test or Fisher's exact test. SAS 9.2 version (SAS Institute, Cary, NC, USA) was used for the statistical analysis. A two-tailed P value that was less than 0.05 was regarded to be statistically significant.

Ethics statement

The study protocol was approved by the institutional review board of Seoul National University Hospital (IRB No. 1201-021-392). Informed consent was waived by the board due to retrospective study without any harm to each study subject.

RESULTS

A total of 34 subjects were diagnosed with primary liver cancer for the first time through a routine health check-up during a period of 8 yr. Only 11.8% of liver cancer subjects had been under previous surveillance (Table 1). Of the liver cancers, 82.4% were detected at a health check-up, and 17.6% were detected by surveillance which had been started after the initial health check-up. Liver cirrhosis was found in 76.5% of the liver cancer subjects. HBsAg was the most commonly found underlying risk factor for liver cancer in our study (55.8%), followed by anti-HCV (17.7%) and heavy alcohol consumption (8.8%). However, 17.7% of the liver cancer subjects did not have any evidence of HBsAg, anti-HCV or heavy alcohol consumption. Mean age was significantly younger in subjects with HBsAg than in those without HBsAg (P = 0.028). Male was about 6 times more common than female. Of the liver cancer subjects, 47.1% had diabetes, and 64.7% were current smokers. Family history of liver cancer was positive in 21.1% of subjects with HBsAg and 16.7% of subjects with anti-HCV. Among 34 liver cancers, 1 intrahepatic cholangiocarcinoma was confirmed by biopsy in a subject with HBV.

Table 1 Baseline characteristics, tumor marker and gross tumor type according to risk factors for primary liver cancer in detected cases in this study

jkms-28-1449-i001

(Click on table to enlarge)

Gross tumor type was significantly different between subjects with HBsAg and those with anti-HCV (Fig. 1). Nodular tumor was more common than infiltrative tumor in subjects with HBsAg, but infiltrative tumor was more common in subjects with anti-HCV. General weakness, weight loss or dyspepsia was significantly more common in subjects with infiltrative tumor than in those with nodular tumor (Table 2). Serum αFP level was significantly higher in subjects with infiltrative tumor than in those with nodular tumor. Metastasis was observed only in 5 subjects with infiltrative tumor, 4 lung metastasis and 1 lymph node metastasis. Surgery was the most common method of treatment for single nodular liver cancer, but transarterial chemoembolization was used for multinodular or infiltrative liver cancer (Fig. 2).

jkms-28-1449-g001

Fig. 1 Differences in gross tumor type according to associated risk factors for primary liver cancer.

jkms-28-1449-g002

Fig. 2 Comparison of treatment methods according to gross tumor type.

jkms-28-1449-i002

Table 2 Differences in general symptom, family history of liver cancer, and metastasis according to gross tumor type

(Click on table to enlarge)

DISCUSSION

Our study showed that a low proportion of the liver cancer subjects had been under previous surveillance for primary liver cancer. Moreover, even though HBV is the most common risk factor in Korea, only 5.3% of HBV positive liver cancer subjects were under surveillance. This result may suggest that the actual surveillance rate may be low in spite of the recommendations by the Korean government since 2001 that regular surveillance of high risk subjects for liver cancer who are older than 40 yr be performed (8). As regular surveillance can improve the morbidity and prognosis of liver cancer, more efforts to enroll subjects at high risk for liver cancer into regular surveillance programs may be needed (14).

A routine health check-up may provide a good chance to detect liver cancer and start surveillance for liver cancer. In our study, 82.4% of the liver cancers were found during a health check-up and 17.6% of the liver cancers were found by surveillance which had been started after a health check-up because the HBsAg or anti-HCV was found to be positive.

In regards to the major risk factor for liver cancer found in our study, HBsAg was the most common factor, followed by anti-HCV and heavy alcohol consumption. The proportion of HbsAg-positive subjects was similar to the previously reported worldwide proportion of 50%-55%, but the proportion of anti-HCV positive subjects was less than the previously reported worldwide proportion of 25%-30% (15). The proportion of anti-HCV in liver cancer subjects in Korea may not have changed for 20 yr when comparing the present data to that (17.0%) published 20 yr ago (16). Considering the previous report that HCV-related hepatocellular carcinoma represents 70% of all primary liver cancers in Japan, the underlying cause of primary liver cancer can vary quite considerably among geographically near countries such as Japan and Korea (16, 17). The liver cancer was accompanied by liver cirrhosis in 76.5% of the subjects with liver cancer, which was a rate similar to the 73.3% figure quoted in a previous report in Korea (18). Of the liver cancer subjects, 64.7% were current smokers in our study. As smoking is known to increase the risk of liver cancer, smoking might contribute to the development of liver cancers (19). In our study, 47.1% of the subjects had diabetes. As diabetes is also recognized as a predisposing factor for liver cancer, diabetes might also have contributed to the development of liver cancer in our subjects (20-22). Our subjects' mean BMI was 24.9 ± 3.5, which was near 25, the cutoff value for being overweight (23). Adequate weight control may be needed in subjects with risk factors for liver cancer because obesity has been shown to have an association with liver cancer (24, 25).

The proportion of subjects without HBsAg, anti-HCV, and heavy alcohol consumption was 17.7%, which is comparable to the figure of 17.6% published 20 yr ago in Korea but is slightly higher than that of 8%-15% in Japan (16, 17). These results suggest that any liver mass found by chance at USG or CT should be thoroughly evaluated even in a subject without positive test results for HBV or HCV, or who does not have heavy alcohol consumption. Among subjects without HBsAg, anti-HCV, and heavy alcohol consumption, 83.3% were smokers and 16.7% were obese in our study. Nonalcoholic steatohepatitis was found in 10% of liver cancer subjects without HBV and HCV in Japan (17). Smoking, nonalcoholic steatohepatitis, aflatoxin or other carcinogenic causes may also be an associated underlying risk factor in these subjects without HBsAg, anti-HCV, or heavy alcohol consumption (26).

Male sex was 5.8 times more common than female in our study. This male predominance coincides with the finding in previous reports (3). Mean age was 59.0 ± 10.1 yr. Mean ages were significantly different according to associated risk factors for liver cancer. Mean age of subjects with HBsAg was 54.5 ± 8.5 yr but that of subjects with anti-HCV was 64.3 ± 10.9 yr, which also coincides with the findings in a previous report (16). Proportion of intrahepatic cholangiocarcinoma may be comparable to a previous study in Japan that reported 95% of primary liver cancers were hepatocellular carcinoma (17).

The general symptoms of weakness, fatigue or dyspepsia were more frequently found in subjects with infiltrative tumor than in those with nodular tumor in our study. Newly occurring general symptoms of weakness, fatigue or dyspepsia in a high-risk subject for liver cancer may need attention because these symptoms may come from a newly developed liver cancer (18).

αFP level was higher in subjects with infiltrative liver cancer than in those with nodular liver cancer. This finding is in concordance with the previous report that αFP reflects tumor activity in hepatocellular carcinoma (27).

A routine health check-up may be a good opportunity to detect liver cancer in an early stage. Single nodular liver cancer was found in 50% of the subjects in our study. On the other hand, the proportion of single nodular cancer among all liver cancers detected was previously reported to be 32.0% and 37.3% in each of two different tertiary hospitals in Korea (18, 28). The reason for this difference in the proportion of single nodular cancer may have two possibilities. First, liver cancers detected at tertiary hospitals were found in subjects with already known high-risk factors for liver cancer by surveillance. Second, liver cancers detected in a routine health check-up are found at a very early stage and this phenomenon may reflect the real effect of screening for liver cancer in a primary care setting. This may be important because detecting a liver cancer in an early or at a single nodule stage can lead to curative treatment. Surgical resection or local ablative therapy has been regarded as a curative therapy (29). A total of 44.0% of our liver cancer subjects received curative therapy: 26.5% of subjects received surgical resection and 17.6% of subjects received local ablative therapy. This may be higher than the 12.4% of subjects who were reported to be curatively treated in a previous report (18). Moreover, considering that transarterial chemoembolization can be a curative treatment if the embolization is compact, the actual proportion of subjects who received curative therapy may be higher than 44.0% in our study (30). Actually, 8.8% of our subjects who had single nodular liver cancer were completely treated by transarterial chemoembolization only or consecutive surgery.

Our study has the limitation of not representing the whole Korean population because the subjects in our study visited the center voluntarily for a routine health check-up. There may be some selection bias in our study because a person with high risks for liver cancer may get their liver evaluated in a liver-specific clinic than in a routine heath check-up center. Our study may also have the limitation of being a retrospective study.

In summary, a routine health check-up may provide 3 important opportunities for detection of liver cancer. The first is the opportunity to detect a liver cancer at a very early stage. The second is the opportunity to start surveillance in high-risk subjects for liver cancer. The third is the opportunity to detect a liver cancer in subjects without the representative risk factors of chronic viral hepatitis or heavy alcohol consumption.

Footnotes

This work was supported by a grant number of 00-2008-03 from Seoul National University Hospital Healthcare System Gangnam Center Research Fund.

The authors have no conflicts of interest to disclose.

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