Sally Caglioti

A new strategy for estimating risks of transfusion-transmitted viral infections based on rates of detection of recently infected donors

BACKGROUND:  Estimates for human immunodeficiency virus (HIV)‐1 and hepatitis C virus (HCV) transfusion‐transmitted risks have relied on incidence derived from repeat donor histories and imprecise estimates for infectious, preseroconversion window periods (WPs).

Virus and Antibody Dynamics in Acute West Nile Virus Infection

BACKGROUND The dynamics of the early stages of West Nile virus (WNV) infection can be assessed by follow-up studies of viremic blood donors. METHODS A total of 245 donors with WNV viremia were followed up weekly for 4 weeks and then monthly for up to 6 additional months or until seroconversion. Plasma samples were tested for WNV RNA by transcription-mediated amplification (TMA) and for WNV-specific IgM and IgG antibodies. RNA persistence was investigated by 6 replicate TMA tests; samples that were viremic for >40 days were tested for WNV-neutralizing activity. Follow up of 35 additional viremic donors for up to 404 days was conducted to evaluate persistence of WNV-specific antibody. RESULTS The median time from RNA detection to IgM seroconversion was 3.9 days; to IgG seroconversion, 7.7 days; to RNA negativity by single-replicate TMA, 13.2 days; and to RNA negativity by 6-replicate TMA, 6.1 additional days after results of single-replicate TMA are negative. For 4 donors in whom RNA persisted for >40 days after the index donation, all samples obtained after this threshold were also positive for WNV IgG and neutralizing activity. The mean times to IgM and IgA negativity were 156 and 220 days, respectively. CONCLUSIONS IgM and IgG develop rapidly after viremia and before RNA levels become undetectable, which occurred a mean of 13.2 days after the index donation among donors in this study. WNV RNA detection by replicate TMA rarely persists for >40 days after the index donation and is accompanied by WNV-specific neutralizing antibody, consistent with an absence of WNV transmission via transfusion of seropositive blood components.

NAT of the United States and Canadian blood supply

Nucleic amplification testing (NAT) has been performed on virtually all blood collected in the United States since early 1999. The testing has been focused on HIV-1 and HCV. HBV NAT versions are being developed for implementation in the future. The impetus for implementing HCV NAT came from the European plasma fractionators whose regulations were changed to require HCV NAT-screened products. Strong impetus in the United States also came from FDA Commissioner, David Kessler, MD, who at a September 1994 workshop urged the industry to develop sensitive NAT assays so that all recipients of blood and blood components could be assured of the safest components possible. Because of the short timeframe associated with the European requirement (in place as of July 1999), and because commercial tests were not automated (and actually not even ready for commercialization), pooled testing using manual (first-generation) technology was adopted.1 NAT is performed under an investigational new drug (IND) application approved by the FDA.2 Two test system vendors, Gen-Probe (San Diego, CA) and Roche Molecular Systems (RMS, Pleasanton, CA), are approved under separate IND applications. The two major goals of the NAT IND applications, independent of their sponsors, have been to show the feasibility of performing NAT in pools and to reduce the window period with regard to the detection of HIV1 and HCV. Before NAT implementation, these window periods were estimated at 16 days after infection for HIV-1 and 70 days after infection for HCV. NAT is estimated to reduce the window period for HIV-1 by 3 to 8 days (<50%) and that for HCV by 41 to 60 days (<85%).3-5 The effect of pooling—that is, dilution—on the window-period reduction has little impact on HCV detection (because of high viral levels that are reached shortly after virus replication begins) but may have a more significant effect on HIV-1 (because of longer ramping-up periods). A subsidiary goal of the HIV-1 NAT study is to show that HIV-1 p24 antigen screening, in place since March 1996, is no longer necessary. Since the implementation of p24 antigen screening at the American Red Cross (ARC), the yield of p24 antigen confirmed-positive donors who are HIV-1 antibody negative has been 6 among more than 24 million donations screened, or 1 in 4,000,000. Because the HIV-1 RNA response detected by NAT occurs before or simultaneously with p24 antigen, and because HIV-1 RNA is detected in plasma long after p24 antigen has disappeared, it may well make sense to eliminate the p24 antigen test as a screening test.6 The p24 antigen test was introduced by the FDA as an interim recommendation (FDA, Center for Biologics Evaluation and Research: memo to all registered blood and plasma establishments, August 8, 1995) giving the industry hope that, once a test for pooled specimens was licensed for NAT, the p24 antigen test might be eliminated.

Chagas disease and the US blood supply.

Purpose of review To describe new developments in blood-bank screening and management of patients with chronic Trypanosoma cruzi infection in the United States. Recent findings The first US Food and Drug Administration licensed serological test for T. cruzi blood screening went into widespread usage in January 2007. More than 500 confirmed T. cruzi-infected donations were detected by mid-June 2008. Until recently, drug therapy was recommended for acute and congenital infections, but seldom for chronic infections, which were believed to respond poorly. However, in the 1990s, efficacy was demonstrated in two placebo-controlled trials of benznidazole in children with chronic T. cruzi infection. In 2006, a nonrandomized, nonblinded trial demonstrated that benznidazole treatment may slow progression of cardiomyopathy and decrease mortality risk in infected adults. Summary Blood-bank screening will continue to detect T. cruzi-infected donors. Based on recent data, antitrypanosomal treatment is recommended for all acute and congenital T. cruzi infections, reactivated infection, and chronically infected children. In adults aged 19–50 years without advanced heart disease, treatment should generally be offered; management should be individualized for older adults. Less toxic, more effective drugs, a sensitive, specific assay for response to treatment, and improved healthcare access would promote more effective management.

Testing Strategy To Identify Cases of Acute Hepatitis C Virus (HCV) Infection and To Project HCV Incidence Rates

ABSTRACT Surveillance for hepatitis C virus (HCV) is limited by the challenge of differentiating between acute and chronic infections. In this study, we evaluate a cross-sectional testing strategy that identifies individuals with acute HCV infection and we estimate HCV incidence. Anti-HCV-negative persons from four populations with various risks, i.e., blood donors, Veterans Administration (VA) patients, young injection drug users (IDU), and older IDU, were screened for HCV RNA by minipool or individual sample nucleic acid testing (NAT). The number of detected viremic seronegative infections was combined with the duration of the preseroconversion NAT-positive window period (derived from analysis of frequent serial samples from plasma donors followed from NAT detection to seroconversion) to estimate annual HCV incidence rates. Projected incidence rates were compared to observed incidence rates. Projected HCV incidence rates per 100 person-years were 0.0042 (95% confidence interval [95% CI], 0.0025 to 0.007) for blood donors, 0.86 (95% CI, 0.02 to 0.71) for VA patients, 39.8 (95% CI, 25.9 to 53.7) for young IDU, and 53.7 (95% CI, 23.4 to 108.8) for older IDU. Projected rates were most similar to observed incidence rates for young IDU (33.4; 95% CI, 28.0 to 39.9). This study demonstrates the value of applying a cross-sectional screening strategy to detect acute HCV infections and to estimate HCV incidence.

Triggers for switching from minipool testing by nucleic acid technology to individual-donation nucleic acid testing for West Nile virus: Analysis of 2003 data to inform 2004 decision making

BACKGROUND:  Concern about West Nile virus (WNV) transfusion‐transmitted infections missed by minipool (MP) nucleic acid testing (NAT) has prompted consideration of the use of individual‐donation (ID) NAT. Strategies were investigated for the application of limited ID‐NAT capacity in 2004.

Analytical and clinical sensitivity of West Nile virus RNA screening and supplemental assays available in 2003.

BACKGROUND: Transfusion‐transmitted West Nile virus (WNV) infections were first reported in 2002, which led to rapid development of investigational nucleic acid amplification tests (NAT). A study was conducted to evaluate sensitivities of WNV screening and supplemental NAT assays first employed in 2003.

Genetic Variability of West Nile Virus in US Blood Donors, 2002–2005

This virus is diverging from precursor isolates as its geographic distribution expands.

Clinical specificity and sensitivity of a blood screening assay for detection of HIV-1 and HCV RNA

BACKGROUND: An HIV‐1 and HCV NAT blood screening assay (Procleix HIV‐1/HCV, Gen‐Probe, Inc.) simultaneously detecting HIV‐1 and HCV RNA) has been implemented. Donor plasma samples reactive in the Procleix HIV‐1/HCV assay are tested with the HIV‐1 and HCV discriminatory assays to resolve whether HIV‐1 RNA, HCV RNA, or both are present.

Epidemiologic and laboratory findings from 3 years of testing United States blood donors for Trypanosoma cruzi

BACKGROUND: At most blood centers in the United States routine testing of donations for Trypanosoma cruzi using an enzyme‐linked immunosorbent assay (ELISA) is followed by supplemental testing by radioimmunoprecipitation assay (RIPA). The objective of this study was to report the results of routine testing and risk factor data from allogeneic blood donors.