On 28-29 October 2014, the European Medicines Agency (EMA) held a meeting on the ‘Viral safety of plasma-derived medicinal products with respect to hepatitis E.’ Dr Joan O’Riordan from the Irish Blood Transfusion Services attended on behalf of the European Haemophilia Consortium (EHC). A full report of this event was circulated by e-mail to all National Member Organisations (NMO) earlier in March. Here below, you will find some of key findings from the event as reported by Dr O’Riordan.
Hepatitis E Virus (HEV) is a small, single-stranded, non-enveloped ribonucleic acid (RNA) virus with four different subtypes of the virus called genotypes 1 to 4 (G1-4). G1 and G2 are human viruses and have caused outbreaks of hepatitis in the developing world due to poor sanitation and contaminated water. G3 and G4 are swine viruses infecting pigs and other species such as wild boar, deer as well as human beings. G3 predominates in Europe.
It was only in the past decade that a number of HEV infections were identified in Europe and the subtype of the virus in these cases was G3 rather than G1 and G2. The very close genetic identity between G3 strains circulating in pigs and humans indicates that HEV G3 infections in humans is a zoonosis, i.e. a disease that is transmitted from animals to humans, through, for example, the consumption of undercooked pork meat.
Hepatitis E infection in healthy individuals is largely asymptomatic and a subclinical infection. The duration of the infectious stage is approximately eight weeks. Not long after the formation of antibodies the virus is cleared. The infectious period in blood donors can be identified by nucleic acid tests (NAT).
Chronic HEV infection
Until recently it was thought that a persistent form of HEV did not occur and that it was like hepatitis A. The realisation that a small number of immunocompromised patients can develop a chronic hepatitis with rapid progression to liver fibrosis and cirrhosis has raised concerns about the transmission of this virus to susceptible patients.
This virus may be cleared after alteration or dose reduction of immunosuppressive therapy and if this is not possible by monotherapy with Ribavirin. Therefore the identification of such patients is a high priority so that intervention can be offered to induce viral clearance.
Transfusions Transmitted HEV Infection
A study of the transfusion population in England (Hewitt et al, 2014) suggests a transmission rate through transfusion of 42 per cent of transfusion recipients with 55 per cent of those developing prolonged or persistent infection. The prevalence of HEV RNA is of one in 2,848 in the study indicates that about 80,000 to 100,000 acute HEV infections occurred in England during the year of the study.
Transfusion Transmission of HEV by Solvent Detergent (SD) treated plasma
The hepatitis E virus is a small, (virus particle 27-34 nanometer (nm) in diameter) non enveloped RNA virus. It is known that solvent detergent (SD) process will not inactivate non-enveloped viruses. It was reported during the workshop that transmissions had been documented in France and in Canada. In recognition of this risk for the SD treated plasma, from January 2015, the European Pharmacopoeia has mandated NAT testing for plasma pools processed with solvent-detergent.
Plasma-Derived Medicinal Products (PDMP)
During the workshop it was stated that HEV RNA was detected in plasma fractionation pools (Baylis et al, 2011) used to manufacture PDMP. However the viral loads were low and a study from Modrow et al, 2011, did not detect HEV RNA in any final preparation of a range of plasma-derived coagulation factor concentrates. Additionally, no reports of transmission of HEV by PDMP was reported and there is no evidence of residual hepatitis risk through the use of PDMP.
With regards to manufacturing, it appears that HEV is not inactivated by low pH but is is inactivated by 80°C dry heating, 60°C pasteurisation and by nanofiltration with a pore size of less or equal to 20 nm. It appears that combining nanofiltration with heating is a robust measure against HEV contamination for PDMP.
For more information about this workshop, please contact the EHC office.