FDA advisory panel decisionsPerspective

FDA panel votes to specify risk for hepatitis E in blood transfusions

The FDA Blood Products Advisory Committee voted unanimously that scientific data indicate a need to characterize the risk for hepatitis E transmission by transfusion in the United States.

Developed countries have reported transmission of hepatitis E virus by transfusion — specifically genotype 3, the genotype found in the United States.

“The risk of hepatitis E infection from blood transfusions in the US is unknown,” Susan Zullo, PhD, of the Office of Blood Research and Review at the FDA, told the panel. “Anti-hepatitis E virus seroprevalence in blood donors and in recipients is unclear and needs further studies.”

There is a period of asymptomatic viremia after initial infection with hepatitis C virus, so blood donors that appear healthy could be infected with the virus and donate blood. According to Zullo, there is a high seroprevalence of anti-HCV in US blood donors, ranging from 13.7% to 31%. The wide variation of the assays used in the studies may explain the differing prevalences observed. The risk for disease potential appears to be higher among immunocompromised individuals, pregnant women and those with pre-existing liver disease, Zullo said. Immunocompetent people are less likely to develop clinical disease.

Although the risk for hepatitis E virus transmission through transfusion is a concern, blood supplies are currently not screened for the disease in the United States, as there are no known FDA-approved diagnostic or blood donor screening tests for hepatitis E.

Zullo said nucleic acid testing (NAT) assays could be characterized using current WHO international standard for hepatitis E virus RNA and a panel of biologically confirmed clinical samples. These assays could be used to perform large-scale prospective studies on blood donors to determine the prevalence of viremic blood donors. This will provide an estimate of the magnitude of the risk for hepatitis E virus exposure and the potential threat to the safety of the blood supply.

Next, serological assays will need to be characterized, using a pedigree panel of biologically confirmed clinical samples for those infected with hepatitis E, Zullo said. This will take longer to achieve, as the pedigree panel needs to be established. Both the validated NAT and serological assays could be used to perform studies on donor and recipient link samples from existing repositories, she said.

According to Scott Holmberg, MD, of the CDC, approximately 20 years ago, a study of 18,700 serum specimens identified a 21% prevalence of hepatitis E virus immunoglobulin G. Researchers at the CDC found that although the assay was sensitive, it was less specific. In a random sample of 6,000 from those original specimens, the prevalence was identified as 17%. However, in a 2008-2009 study of 8,000 specimens, the seroprevalence decreased threefold to about 6.4%, according to Holmberg.

“We think there is a reduction in exposure, which is going to make finding out where the exposure is coming from more difficult,” Holmberg told the panel.

Several studies have shown that eating undercooked pork is associated with hepatitis E virus. However, Holmberg said the problem with this hypothesis is that, in the United States, pig products are rarely consumed raw or undercooked. Also, the CDC studies did not find a substantial difference in the incidence of hepatitis E virus between those who do not eat pork and those who do.

As far as blood transfusions, Holmberg said, in one study, participants with hepatitis E were asked if they ever received a blood transfusion. In those who had, the seropositivity rate was 9.4%, whereas in those who had not, the seropositivity rate was 8.9%.

The FDA Blood Products Advisory Committee voted unanimously that scientific data indicate a need to characterize the risk for hepatitis E transmission by transfusion in the United States.

Developed countries have reported transmission of hepatitis E virus by transfusion — specifically genotype 3, the genotype found in the United States.

“The risk of hepatitis E infection from blood transfusions in the US is unknown,” Susan Zullo, PhD, of the Office of Blood Research and Review at the FDA, told the panel. “Anti-hepatitis E virus seroprevalence in blood donors and in recipients is unclear and needs further studies.”

There is a period of asymptomatic viremia after initial infection with hepatitis C virus, so blood donors that appear healthy could be infected with the virus and donate blood. According to Zullo, there is a high seroprevalence of anti-HCV in US blood donors, ranging from 13.7% to 31%. The wide variation of the assays used in the studies may explain the differing prevalences observed. The risk for disease potential appears to be higher among immunocompromised individuals, pregnant women and those with pre-existing liver disease, Zullo said. Immunocompetent people are less likely to develop clinical disease.

Although the risk for hepatitis E virus transmission through transfusion is a concern, blood supplies are currently not screened for the disease in the United States, as there are no known FDA-approved diagnostic or blood donor screening tests for hepatitis E.

Zullo said nucleic acid testing (NAT) assays could be characterized using current WHO international standard for hepatitis E virus RNA and a panel of biologically confirmed clinical samples. These assays could be used to perform large-scale prospective studies on blood donors to determine the prevalence of viremic blood donors. This will provide an estimate of the magnitude of the risk for hepatitis E virus exposure and the potential threat to the safety of the blood supply.

Next, serological assays will need to be characterized, using a pedigree panel of biologically confirmed clinical samples for those infected with hepatitis E, Zullo said. This will take longer to achieve, as the pedigree panel needs to be established. Both the validated NAT and serological assays could be used to perform studies on donor and recipient link samples from existing repositories, she said.

According to Scott Holmberg, MD, of the CDC, approximately 20 years ago, a study of 18,700 serum specimens identified a 21% prevalence of hepatitis E virus immunoglobulin G. Researchers at the CDC found that although the assay was sensitive, it was less specific. In a random sample of 6,000 from those original specimens, the prevalence was identified as 17%. However, in a 2008-2009 study of 8,000 specimens, the seroprevalence decreased threefold to about 6.4%, according to Holmberg.

“We think there is a reduction in exposure, which is going to make finding out where the exposure is coming from more difficult,” Holmberg told the panel.

Several studies have shown that eating undercooked pork is associated with hepatitis E virus. However, Holmberg said the problem with this hypothesis is that, in the United States, pig products are rarely consumed raw or undercooked. Also, the CDC studies did not find a substantial difference in the incidence of hepatitis E virus between those who do not eat pork and those who do.

As far as blood transfusions, Holmberg said, in one study, participants with hepatitis E were asked if they ever received a blood transfusion. In those who had, the seropositivity rate was 9.4%, whereas in those who had not, the seropositivity rate was 8.9%.

    Perspective
    Michael Busch

    Michael Busch

    Hepatitis E is a transient infection in most people, but in immunocompromised individuals, it can cause chronic infection. There have been a few instances of transfusion-transmitted hepatitis E in Europe and Japan, but not in the United States. The question is whether we have we been missing transmission by transfusion because we haven’t been focusing on it. The FDA convened the advisory committee to discuss the data about the prevalence of the infection and the risk of transfusion transmission. The general take-home message from the meeting is that we should do additional studies to understand what the rate of infection is in donors and further research if those studies show any significant rates of affected donors. The Red Cross is launching a 20,000 donor study to look for hepatitis E nucleic acids in their blood donations. The company Hologic/Gen-probe has a partnership with Novartis, and they are coming up with an assay that includes testing for hepatitis E virus. If the results from the prevalence study show any significant rates of hepatitis E RNA positivity in current US donors, then we would proceed to study whether the RNA positive units actually infect patients when transfused. My personal expectation is that we will not find any significant rates of viremia in US donors. The CDC data from serosurveys have shown that the rate of hepatitis E has dropped from 20% to 5%. Age stratification studies have shown that older people have a much higher probability of having the antibodies that indicate prior exposure. It looks like the virus is being spread much less today than in the past.

    • Michael Busch, MD, PhD
    • Director, Blood Systems Research Institute

    Disclosures: Dr. Busch is on the scientific advisory board of Gen-Probe and has received research funding from Novartis.