Study helps characterize HCV exacerbation course, outcomes

By: SHARON WORCESTER,  Oncology Report Digital Network

09/01/13

Most patients who experience an acute exacerbation of chronic hepatitis C achieve a sustained viral response after treatment with pegylated interferon and ribavirin, a long-term case-control follow-up study shows.

Of 82 consecutive patients who had an acute exacerbation of chronic hepatitis C virus (HCV) between January 2005 and June 2010, 32 were treated with peg-IFN and ribavirin, and 26 of those (81.2%) achieved a sustained viral response (SVR); of 82 control subjects with HCV who did not experience an acute exacerbation, 38 were treated with peg-IFN and ribavirin, and 23 of those (60.5%) achieved an SVR, Dr. Evangelista Sagnelli of Second University of Naples, Italy, and her colleagues reported online April 15 ahead of print in Clinical Gastroenterology and Hepatology.

The case patients, who were a mean age of 50 years, were anti-HCV/HCV RNA positive, hepatitis B surface antigen (HBsAG)/anti-HIV–negative patients who were naive to anti-HCV therapy. HCV genotype 1 was detected in 43.9% of cases, and genotype 2 was detected in 46.4% of cases.

The patients, who were followed for a median of 36 months after a 2-month observation period, were matched to 82 controls based on age, sex, and disease genotype. The controls, who were followed for 32 months, were HBsAG-negative patients who never showed signs of symptomatic acute exacerbation; they had steady alanine aminotransferase (ALT) values at four checks per year over the prior 5 years. They also were anti-HCV therapy-naive.

More case patients than control patients carried the interleukin-28B CC genotype (40.2% vs. 24.4%).

"In several determinations over the years before reactivation, these 82 patients had been HCV RNA positive with normal or moderately increased serum alanine aminotransferase levels, suggesting an indolent, slowly progressing course of chronic hepatitis C," the investigators said.

They had a mean aspartate aminotransferase (AST) serum value of 672 IU/dL, a mean ALT serum value of 1063 IU/dL, and a total bilirubin level of 15.87 mg/dL, the investigators said (Clinical Gastroenterology and Hepatology 2013 [doi:10.1016/j.chg.2013.03.025]).

In 43.5% of cases, ALT increased steadily to at least twice the baseline value, but more than half of these (56.5%) experienced a return to baseline values prior to the acute exacerbation, they noted.

A comparison of biopsy specimens showed increasing fibrosis in 78.3% of 23 cases, compared with 38.7% of 31 controls with biopsies available. Fibrosis scores remained stationary in 21.7% of the case patients, and in 58.1% in the control group. Only one patient in the control group (3.2%) improved.

Additionally, histologic activity index (HAI) scores deteriorated by at least 2 points in 60.9% of cases, compared with 9.7% of controls.

"An improvement in the HAI of at least 2 scores was found only in 4 (12.9%) in the control group patients, whereas 9 patients (39.1%) in the case group and 24 patients (77.5%) in the control group remained stationary," the investigators said.

This study, which was designed to better characterize the clinical presentation and course of symptomatic acute exacerbation of chronic hepatitis C, as well as outcomes and response to antiviral therapy, improves "the scanty knowledge" on these topics, they said.

The findings demonstrate marked variability in the clinical presentation, with ALT levels ranging from 6- to 43-fold the normal values, and serum bilirubin increases ranging from 2 to 22 mg/dL.

The investigators also observed that although the clinical course of acute exacerbations was usually characterized by a single flare, in some cases more than one flare occurred, and that acute exacerbations can occur at any age; in this study they occurred in patients ranging in age from 24 to 87 years.

Furthermore, the observation that nearly half of the study patient with an acute exacerbation showed HCV genotype 2 confirms the association between exacerbation and genotype 2 demonstrated in previous studies, they said.

"The reasons for this association remain unknown and warrant further investigation," they said, noting that exacerbations in the current study were also common among those with HCV genotype 1, but were rare in other HCV genotypes.

The unexpectedly higher prevalence of genotype IL-28-B CC in the case patients in this study "may suggest a greater likelihood of developing acute exacerbation of chronic hepatitis C for patients with the genotype," they said, noting that this observation also deserves additional study.

"Most probably acute exacerbation of chronic hepatitis C is a consequence of a reactivation of cell-mediated immune reaction to clear HCV infection, in some ways in line with the well-known propensity of IL-28-B CC genotype to undergo a spontaneous or treatment-induced clearance of HCV infection," they said.

Another observation in this study is that acute HCV exacerbation frequently causes deterioration both in fibrosis and necroinflammation – a finding that underscores "the profound implications of acute exacerbation of chronic hepatitis C on the progression to cirrhosis and risk of hepatocellular carcinoma," they said.

"In conclusion ... acute exacerbation of chronic hepatitis is responsible for an unfavorable outcome in patients with chronic hepatitis. However, the majority of patients with acute exacerbation of chronic hepatitis C obtained an SVR, most probably because of the high frequency of HCV genotype 2 and IL-28-B CC genotypes in the case group, and possibly because the reactivation of a cell-mediated immune response may favor HCV clearance," they said, adding that "the more rapid progression to cirrhosis and the risk of hepatocellular carcinoma strongly warrant the early initiation of anti-HCV therapy for acute exacerbation of chronic hepatitis C patients."

In this study, such patients showed "an impressive rate of SVR to peg-IFN + ribavirin," they said.

This study was supported by grants from PRIN 2008, MIUR, Rome, Italy, "Ottimizzazione Della Diagnosi Eziologica dell’epatite Acuta C E Studio dei Fattori Viro-Immunologici di Guarigione, di Cronicizzazione E di Risposta Alla Terapia Con Interferone," and Tegione Campania "Progetti per il miglioramento della qualita dell’assistenza, diagnosi e terapia del paziente afetto da AIDS nei settori: immunologia, coinfezioni, informazione e prevenzione," 2008. The authors reported having no disclosures.

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Smart syringe turns red to tell you it's been used

By Holden Frith, for CNN

updated 11:17 AM EDT, Tue September 3, 2013 | Filed under: Innovations

The ABC Syringe turns dark red after use, warning doctors and patients that it may be contaminated

Editor's note: Every two years, the prestigious INDEX: Awards seek out designers working on innovative solutions to global challenges. In this special CNN series, we profile a selection of the nominees.

(CNN) -- Of the four to five billion injections given each year in India, at least 2.5 billion are unsafe, according to one study. In some cases, that means they are administered using unsterilized second-hand syringes that could be contaminated with a blood-borne disease such as hepatitis or HIV.

A simple change to the way syringes are made could dramatically reduce those figures and save thousand of lives each year, according to David Swann of Huddersfield University, in England. His design for a new kind of syringe that changes color after it has been used was nominated for an INDEX: Award.

"1.3 million people (globally) a year die from unsafe injection practices," Swann says, quoting WHO figures. "It accounts for over 30% of hepatitis A and B cases and 5% of HIV cases."

He explained that in India it is common for scavengers to hunt through landfill sites looking for old syringes that they can clean up and sell to clinics.

"When you compare a sterile syringe just out of its packaging with a syringe that's been washed, how do you determine the difference?" he said. "We conceived an intelligent ink that, if exposed to air by taking it out of the package or if the package is breached that would activate it and turn it red."

The ABC Syringe is impregnated with an ink that's sensitive to carbon dioxide and then sealed in a protective atmosphere so that it remains transparent until it is ready for use. After the seal is broken, the shell of the syringe starts to turn a dark red, alerting both doctors to the risk that the syringe may already have been used.

Swann's intention is that the introduction of the ABC syringe should be accompanied by a public information campaign so that patients would also associate a red syringe with danger and would be able to insist on sterile equipment.

"We had to be really quite clever in looking at technologies that cost next to nothing, and modified-air packaging is one of those technologies," Swann said. "It only adds 1% to the retail price, so on a two-and-a-half pence (four cents) syringe it becomes quite an interesting proposition."

According to Swann's calculations, if the ABC syringe is used for 5% of injections administered in India, after five years it will have prevented more than 700,000 infections and saved $130 million in medical costs.

Denis Maire, who works for the World Health Organization's health systems and innovation taskforce, said the ABC Syringe could help to make injections safer.

"Anything that can contribute to decrease the reuse of syringes is worth considering and cost is certainly a major factor," he said. "The great advantage of this concept is that not only health care workers but also patients can have a visual appreciation on the safety status of the device. In my view this could be a good deterrent for practitioners to reuse."

However, he noted that it would be possible for unscrupulous doctors to override the visual warning if their patients did not know the meaning of the color change. He also said that the one-minute delay before the syringe turned red may not be long enough.

"How would you distinguish good and bad syringes if the injections are not practised inside this lap of time?" he said. "It could create confusion and render the concept ineffective."

Ravi Naidoo, a member of the INDEX Award jury and the managing director of Design Indaba, an agency that aims to put creative ideas into practice, said that working with the international medical community would help to turn the prototype into a viable product.

"This innovation speaks to the endless possibilities of design, creativity and innovation in addressing real-world issues," he said. "In addition to being cost-effective, which will ensure the accessibility of the solution, it also allows patients to take charge of a critical issue — great example of empowerment through smart design."

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Study Examines Ways to Restore Immunity to Chronic Hepatitis C Infection

Released: 9/3/2013 11:25 AM EDT
Source Newsroom: Nationwide Children's Hospital

Newswise — The hepatitis C virus hijacks the body’s immune system, leaving T cells unable to function. A new study in animal models suggests that blocking a protein that helps the virus thrive could restore immune function, allowing the body to fight infection. The work, led by teams at The Research Institute at Nationwide Children’s Hospital and Emory University, was published online Aug. 26 in the Proceedings of the National Academy of Sciences.

Previous studies show that antibody treatments that inhibit the protein, called programmed cell death 1 (PD-1), can shrink tumors in humans. This new work suggests that anti-PD-1 antibodies might be equally effective in treating hepatitis C and other persistent human viral infections, says Christopher Walker, PhD, a senior author on the study and director of the Center for Vaccines and Immunity at Nationwide Children’s.

PD-1 is a regulatory protein that helps keep the immune system in check. Normally, PD-1 acts as a switch to turn off immune responses when an infection is under control. Some viruses such as HCV manipulate the PD-1 off switch so that T cells lose their ability to fight the infection, a condition scientists call “T-cell exhaustion.” The result is life-long persistence of HCV in the liver, which increases the risk of cirrhosis, liver cancer and other serious diseases.

The researchers treated animal models with persistent HCV infection with repeated doses of an anti-PD-1 antibody. Although the responses were mixed, one animal did show a dramatic increase in HCV-specific T cell activity in the liver and a sharp decrease in viral load. A closer examination of the data found that the animal had more HCV-specific T cells in the liver before therapy, which could mean that therapeutic success hinges on the amount of HCV-specific T cells in the liver before treatment.

“Our supposition is that these T cells remained in the liver for years at levels too low to detect before treatment, and had the capacity to expand after treatment,” Dr. Walker says. “The animal that responded to therapy had a broad, strong response during the early acute phase of infection. This suggests that one predictor of response to an anti-PD-1 antibody is the quality of the T-cell response when the initial infection occurs.”

Another interesting finding was the impact of the antibody on CD4+ T cells, helper cells that promote the development of killer T cells called CD8+, which target and destroy virus-infected liver cells. One hallmark of chronic HCV is the collapse of CD4+ cells.

“We have no information on whether PD-1 signaling is a primary mechanism for silencing helper cells, so recovery of the CD4+ helper cell response in this instance provides some indirect evidence that PD-1 signaling also impairs the helper cells,” Dr. Walker says.

Because much of the research focus on HCV is now directed at developing antiviral therapies, it’s likely that these new findings may have a greater impact on treatments for chronic hepatitis B (HBV), rather than the virus studied in this experiment, Dr. Walker says.

“Chronic hepatitis B is an even larger public health problem than HCV and direct-acting drugs control but do not eliminate the virus,” he says. “Immune reconstitution is the holy grail for HBV.”

Toward that end, Dr. Walker’s team plans to explore the insight this new study provides into why anti- PD-1 antibody therapy sometimes succeeds and sometimes fails. Specifically, they want to know what role the quality of T-cell immunity before treatment plays in therapeutic response.

“There is wide variation in the strength of T-cell immunity when people are first infected with the virus, ranging from very strong and sustained to none,” notes Dr. Walker, who also is a professor of pediatrics and molecular virology, immunology, and medical genetics at The Ohio State University.

“Those with very strong sustained responses tend to clear the virus. Anything less, and the virus persists,” Dr. Walker says. “This study suggests that if your T-cell response to the initial infection is good, but not enough to clear the virus, then you may respond to PD-1 blockade years later. If your initial acute phase T cell response is limited and weak, there is less opportunity for PD-1 blockade to work.”

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Maternal transmission cause of HCV in children

Provided by Healio

Indolfi G. J Pediatr. 2013;doi:10.1016/j.jpeds.2013.06.077.

September 4, 2013

Mother-to-child transmission is the leading causes of hepatitis C virus infection in children, according to recent findings published in The Journal of Pediatrics.

“Mother-to-child transmission of HCV is defined as transmission occurring during pregnancy or in the perinatal period from the HCV-infected mother to the fetus or to the child,” according to background information in the study. “The exact timing and the ultimate mechanism of mother-to-child transmission of HCV infection are unknown. Among children acquiring infections from the mother, only a few have been found to be HCV-RNA positive in the first days of life.”

Transmission of HCV is more likely to occur if the mothers had a history of IV drug use, were coinfected with HIV, and had higher liver disease activity as defined by the presence of elevated aminotransferase levels. The major risk factors for perinatal transmission of HCV were shown to be dependent on peripheral blood mononuclear cell (PBMC) infection with HCV.

“HCV-infected maternal PBMCs can be the carrier of the virus inside the child, serving as a Trojan horse for HCV entry,” researchers wrote. “Once inside the child, the efficiency of transmission is dependent on the infection of newborn target cells that in turn is related to the persistence of maternal-infected cells in fetal/neonatal blood.”

However, because transmission is not completely understood, no effective prevention intervention is currently available.

”Perinatal transmission of HCV is a complex and almost unexplained phenomenon,” Giuseppe Infoldi, MD, of Meyer Children’s University Hospital of Florence, told Infectious Diseases in Children. “Further research and attention by clinicians is needed in the future for the leading route of acquisition of HCV infection in children.”

Disclosure: The researchers report no relevant financial disclosures.

Giuseppe Indolfi, MD, can be reached at Meyere Children’s University Hospital of Florence, Viale Pieraccini 34, I-50139, Florence, Italy; email: g.indolfi@meyer.it

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