NAT and blood safety: what is the paradigm?

Over the past two decades, the pendulum of blood safety policy has swung wide and hit hard. Intense criticism of delayed responses to the early clues of the transfusion AIDS epidemic and of tolerance to the long-standing problem of posttransfusion hepatitis has had enormous repercussions.1 Blood collection systems in a number of countries have been completely restructured. Policy makers and physicians have gone to jail. Over the past 10 years, the working paradigm has shifted toward “the precautionary principle” and the elusive mirage of a “zero-risk” blood supply. However, recent commentary on the precautionary principle suggests that even this conservative approach must not seek zero risk or involve disproportionate responses, but rather should incorporate scientific data, consistency with comparable situations, and cost-benefit analyses into precautionary decision making.2 In this issue of TRANSFUSION, a number of articles on NAT for infectious agents illustrate some of the very different factors that have driven the formulation of blood safety policy: perception, science, ethics, international politics, and economics. A review of the data and of the issues raised in these articles presents the opportunity to discuss the recent evolution of blood safety decision making and thus to attempt to answer, or better yet influence, the question posed in the title of this editorial. NAT of whole-blood donations has been in place in the United States since early 1999. The article by Stramer et al.3 reports the results of testing minipools of 16 to 24 plasma samples under Investigational New Drug Application (IND) clearances from the FDA. As of June 2000, the major programs in the United States have tested 16.3 million donations for HCV RNA and 12.6 million for HIV RNA. A total of 62 donations (1/263,000 screened units) were confirmed to be positive for HCV RNA and negative in serologic testing. Similarly, 4 HIV RNA-positive, serologically negative donations (1/3,150,000) were identified. Each of these donations could well have infected two to three recipients. Although many of the participating blood centers were operating in Phase I conditions (i.e., components could be issued before the availability of NAT results), only one (HCV) NAT-positive component was transfused. With regard to specificity, the false-positive rate (i.e., unconfirmed NAT-reactive donations) was only 1 in 15,800 units, better than even the best of serologic screening assays. Thus, despite fears to the contrary, the phase-in of NAT screening has occurred efficiently and without compromise to the availability of the blood supply. This is truly remarkable when one recognizes that the implementation of NAT required the building of specially designed and equipped NAT laboratories and the development of new procedures to obtain donor consent and to collect and rapidly transport specimens to regional NAT laboratories. In addition, technologists were trained in molecular biology techniques; complex new data-management systems for sample pooling, resolution, and supplemental testing of reactive pools were developed; and NAT results were integrated into donor screening and inventory management systems. It also required NAT manufacturers with limited experience in the blood screening arena to scale-up instrument and reagent production capacity and technical support services to support the testing and release of approximately 50,000 donations per day in the United States. It is hard to escape the conclusion that this program represents an enormous accomplishment and that the benefits of accelerated implementation of NAT have outweighed the risks. Furthermore, data are emerging that show that the yield of minipool NAT has been entirely consistent with projections derived from incidence/window period model-based estimates3-7 (also: Kleinman S, et al. Unpublished observations). These observations should enhance our confidence in the ability of modeling strategies to estimate the current risk of the blood supply, and to predict the yield of individual-donation NAT over minipool NAT and the yield of NAT assays for HBV and for other infectious agents in the future. Nevertheless, Sherman8 raises a number of ethical concerns and cautions about the US NAT programs, cogently reminding us that “no harm, no foul” is not an appropriate position to take when medical ethics are considered. He questions whether the approach of essentially universal introduction of NAT while the assay was unlicensed was justified, given the very low projected yield of the tests and the complex ramifications of this unprecedented implementation process. He raises a number of ethical and medicolegal concerns, including issues around donor and recipient informed consent and cost reimbursement for an unlicensed procedure. He is particularly critical of the Phase I testing during which cellular components have been released into hospital inventories on the basis of licensed serologic test results before completion of NAT. NAT and blood safety: what is the paradigm?