In Focus
How much additional safety does anti-HCV serology provide when individual-donation NAT is already in place?
Balancing HCV screening and residual risk
Josephine Mitchell
South African National Blood Service (SANBS), Johannesburg, South Africa
Individual donation nucleic acid testing (ID-NAT) has substantially improved the detection of infectious hepatitis C virus (HCV) donations.
Nevertheless, international guidance continues to recommend anti-HCV antibody screening, including in settings where NAT is already implemented. We provide an overview of an international study examining whether anti-HCV testing provides meaningful additional protection when used alongside ID-NAT.
The question is particularly relevant because HCV epidemiology and testing strategies are changing. A proportion of infected individuals spontaneously clear the infection. Furthermore, effective direct-acting antiviral therapies now achieve cure rates exceeding 95% among successfully treated patients. In highly endemic countries, individuals permanently deferred on the basis of a history of HCV infection could also have implications for enhancing donor and donation availability. The remaining concern is whether anti-HCV-positive, NAT-negative donations may occasionally contain very low levels of virus that escape routine NAT detection.
The first phase of the study analyzed 500 frozen plasma samples that were anti-HCV positive but NAT negative. Samples originated from three countries: 370 from the United States, 100 from South Africa and 80 from Spain. An additional 100 samples that were negative for both anti-HCV and NAT were included to investigate the possibility of false-negative results. The anti-HCV-positive/NAT-negative samples underwent extensive replicate testing using two HCV NAT assays.
Fifteen of the 500 samples showed reactivity in at least one replicate. Reactivity varied considerably among samples, but viral loads were generally extremely low. Most estimated viral loads were below one copy per millilitre, with only one sample demonstrating comparatively greater reactivity, although its estimated viral load was still very low. The investigators then estimated the probability of transfusion transmission using the lowest viral load, which represented the worst-case scenario. Because red blood cell components contain considerably less residual plasma than plasma products, the estimated risk differed substantially between components. Across the 500 samples, the estimated average transmission probability was approximately 0.1% for red blood cell transfusions and 0.83% for fresh frozen plasma. The country-specific estimates also differed, largely reflecting differences in the prevalence of anti-HCV-positive/NAT-negative donations.
Table 1: Average probability of HCV transmission risk across 500 donor samples
The findings suggest that a small proportion of anti-HCV-positive donations may contain very low levels of detectable HCV that become apparent only through intensive replicate testing rather than through routine screening. Nevertheless, the estimated overall transfusion risk was extremely low. The study therefore supports the concept that the incremental safety benefit of anti-HCV testing alongside ID-NAT may be small, although the magnitude of this benefit depends on local epidemiology and testing practices. An important limitation is that the study used an HCV assay with lower sensitivity than the corresponding more sensitive multiplex assay. Consequently, some estimates may have been higher had the more sensitive platform been used. The study should therefore not be interpreted as definitive evidence that anti-HCV testing can universally be discontinued. Instead, the findings support a risk-based approach. Transmission risk estimates differed between countries, emphasizing the importance of evaluating local epidemiology, NAT methodology, component processing and other blood safety interventions before changing national policies.
The study illustrates a broader question facing transfusion services worldwide: as increasingly sensitive technologies become standard, should historical layers of screening remain necessary? Answering that question requires careful assessment of the incremental benefit of each test, the residual risk that remains after NAT and the consequences of changing the testing algorithm. The study provides useful multinational evidence to inform that discussion.
