Detection of TT Virus DNA in Plasma-Derived Clotting Factor Concentrates

To The Editor:

Clotting factor concentrates such as factor VIII and factor IX have been used as replacement therapy in patients with hemophilia to control hemorrhagic episodes. Since around 1980, when the delayed announcement of possible human immunodeficiency virus (HIV) contamination in such products became a serious social problem in Japan, patients with hemophilia have been concerned about various viral contamination of blood products.

Recently, an unenveloped, single-stranded DNA virus, named the TT virus (TTV), was identified as a transfusion-transmissible agent reported to be associated with non–A-G hepatitis.1 The reported prevalence rates of TTV have varied widely, depending on the primers used in the polymerase chain reaction (PCR) detection system. The primer set used by Takahashi et al2 is 10 to 100 times more sensitive than the one described by Okamoto et al,3 which is commonly used. Takahashi et al2 detected TTV DNA in 92 (92%) of 100 individuals at a routine health screening, suggesting that TTV is not pathogenic.

In our hospital, 3 brands of plasma-derived clotting factor concentrates are available (Table 1). We measured TTV DNA in the products using the most sensitive of Takahashi’s primer set.2 For viral inactivation, ion-exchange chromatography, nano-filtration (35 nm), and dry heat at 65°C for 96 hours are unlikely to be sufficient for complete elimination of TTV DNA, although infectivity of attenuated virions might be diminished or lost. Immunoaffinity chromatography, which was designed for selection of targeted materials using monoclonal antibodies, is likely to achieve complete elimination of TTV DNA.

Unenveloped viruses tend to be more difficult to inactivate than enveloped viruses. Enveloped viruses, such as vesicular stomatitis virus (VSV) and Sindbis virus, are easily inactivated, whereas unenveloped viruses, such as ECHO virus and poliovirus, are not inactivated by solvent/detergent treatment. Some viruses, such as parvovirus, are thought to be resistant to heat.4 TTV, an unenveloped and putative parvovirus-like virus,3 may be resistant to methods commonly used for viral inactivation. Immunoaffinity chromatography may be recommended for the elimination of viruses resistant to inactivation.