Journal of Hepatology
Volume 51, Issue 4 , Pages 798-809, October 2009

Transfusion-transmitted hepatitis B virus infection☆

  • Daniel Candotti

      Affiliations

    • National Health Service Blood & Transplant, Cambridge Blood Centre, Long Road, Cambridge CB2 2PT, UK
    • Corresponding Author InformationCorresponding author. Tel.: +44 1223 548138; fax: +44 1223 548155.
    • ,
  • Jean-Pierre Allain

      Affiliations

    • Department of Haematology, University of Cambridge, Cambridge, UK

published online 10 June 2009.

Associate Editor: M. Colombo

Article Outline

Hepatitis B virus (HBV) remains a major risk of transfusion-transmitted infection due to the pre-seroconversion window period (WP), infection with immunovariant viruses, and with occult carriage of HBV infection (OBI). Reduction of HBV residual risk depends upon developing more sensitive HBV surface antigen (HBsAg) tests, adopting anti-HBc screening when appropriate, and implementing HBV nucleic acid testing (NAT), either in minipools or more efficiently in individual samples. HBV NAT combines the ability to significantly reduce the window period and to detect occult HBV carriage substantiating decades of clinical observation that HBsAg-negative/anti-HBc-positive blood could transmit HBV. Clinical observations suggest limited transmission rate of occult HBV compared to WP. Low transmission rate might be related to low viral load observed in OBIs or to the presence of mutants associated with occult carriage. OBIs carrying detectable anti-HBs (∼50%) are essentially not infectious by transfusion. However, recent data suggest that the neutralizing capacity of low anti-HBs may be inefficient when overcome by exposure to high viral load. Anti-HBc blood units without detectable anti-HBs appear moderately infectious except in immunocompromised recipients. Immunodeficient elderly and patients receiving immunosuppressive treatments may be susceptible to infection with lower infectious dose even in the presence of anti-HBs. The immune status of blood recipients should be taken into consideration when investigating “post-transfusion” HBV infection. Pre-transfusion testing and post-transfusion long-term follow-up of recipients, and molecular analysis of the virus infecting both donor and recipient are critical to definitively incriminate transfusion in the transmission of HBV.

Keywords: Hepatitis B virus, Transfusion, Transmission, Occult HBV infection, Immunosuppression

Abbreviations: HBV, hepatitis B virus, WP, window period, OBI, occult HBV infection, HBsAg, HBV surface antigen, NAT, nucleic acid testing, EIA, enzyme immunoassay, ELISA, enzyme-linked immunosorbent assay, CLIA, chemiluminescence immunoassay, CLEIA, chemiluminescent enzyme immunoassay, FFP, fresh-frozen plasmas, RBC, red blood cells, PC, platelet concentrates

 

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1. Introduction 

Hepatitis B virus (HBV) remains a major public health problem worldwide. In highly endemic areas (⩾8% HBsAg prevalence) including Sub-Saharan Africa, South East Asia, China and the Amazon Basin, transmission occurs essentially vertically or horizontally at young ages, and 70–90% of the adult population has serologic evidence of prior infection (anti-HBc). Countries from the Mediterranean area, Eastern Europe and the Middle East with intermediate endemicity (2–7% HBsAg) have a mix of vertical, horizontal, health-care-related (i.e. blood transfusion), unsafe injections, and sexual routes of transmission. In areas of low endemicity (<2% HBsAg) including Western and Northern Europe, North America, part of South America, and Australia, transmission occurs mainly among young adults through sexual contacts or unsafe injections [1].

Before 1970, approximately 6% of multi-transfused recipients acquired transfusion-transmitted HBV. Over the last four decades, the risk of transfusion-transmitted hepatitis B virus has been steadily reduced, yet HBV transmission remains the most frequent transfusion-transmitted viral infection. The residual risk of HBV transfusion transmission is mainly related to blood donations negative for HBsAg that have been collected either during the pre-seroconversion ‘window period’ (WP) defined as the time between infection and detection of a viral antigen or antibody marker, or during the late stages of infection. Implementation of HBV DNA screening has the potential to significantly reduce the WP and to reveal ‘occult’ HBV infection or carriage (OBI) [2]. OBI is defined as the presence of HBV DNA without detectable HBsAg outside the WP. It is generally admitted that pre-seroconversion WP infections are most likely to transmit HBV but transmission from occult HBV infection remains debated [3].

The aim of the present review is to examine the residual risk of transfusion-associated HBV transmission according to HBV screening strategies of blood donations, and the infectivity of HBV-containing blood products according to the immune status of recipients.

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2. Detection of HBV in blood donors 

2.1. Improvements and limitations of HBsAg testing 

HBsAg tests remain the first-line of blood screening for HBV. Current HBsAg screening assays are enzyme immunoassays (EIAs), including enzyme-linked immunosorbent assays (ELISAs), and chemiluminescence immunoassays (CLIAs). These different assays have sensitivity ranging between <0.1 and 0.62ng of HBsAg per mL (1ng/ml corresponds to approximately 2IU/mL) [4], [5]. A chemiluminescent enzyme immunoassay (CLEIA) prototype has been developed that claims a sensitivity of 0.22mIU/mL and the ability to reduce the WP by ∼17 days compared to the CLIA systems in use [6].

Due to high cost and considerable equipment requirements, these HBsAg assays may not be affordable for small-scale blood services particularly in resource-limited developing countries. Rapid immunochromatographic HBsAg tests have been developed and were evaluated in high prevalence areas [7], [8], [9]. Comparative studies showed that rapid tests are less sensitive than most EIAs [7], [8], [10].

Differences in analytical sensitivity and specificity in detection of HBsAg from viruses of different genotypes have been reported among commonly used EIAs [11], [12]. Mutations associated with conformational and hydrophobic changes within and outside the immunogenic major hydrophilic region (MHR) of the S antigen (the main target for capture antibodies used in diagnostic tests) and with reduced synthesis or secretion of HBsAg may account solely or in conjunction for the failure or a significant decrease in detecting HBsAg by immunoassays [13]. Mutations may occur naturally from escaping active or passive immunity or antiviral therapy. Occurrence of such mutant strains may reach ∼30% in areas of high endemicity following vaccination programs [14], [15]. Another cause of failure in detecting HBsAg may be the concomitant presence of hepatitis B surface antibodies (anti-HBs) leading to the formation of circulating immune complexes not or poorly displaced by HBsAg capture antibodies [16], [17].

HBsAg-positive/HBV DNA-negative samples are found in 2–16% of blood donor carriers [10], [18], [19]. Documented cases of donors confirmed HBsAg-positive a few days after HBV vaccination were reported as a cause of unnecessary deferral of blood donors [20], [21]. As a result blood donation within a month from receiving HBV vaccination is discouraged.

2.2. Anti-HBc testing 

Anti-HBc screening for blood donation was initially introduced in the mid 1980s as a surrogate marker for non-A, non-B hepatitis. The 40% efficacy was made totally redundant with the implementation of specific antibodies to hepatitis C virus. After being argued as useful to blood safety as a “lifestyle” marker targeting homosexual men and intravenous drug abusers, it was maintained where implemented as improving HBV safety.

Several studies conducted in Europe and in North America showed that approximately 90% of blood donors carrying anti-HBc also carried anti-HBs signalling recovered HBV infection with a frequency of approximately 90% [10]. The remaining 10% carried either false-positive anti-HBc in a relatively high proportion due to poor assay specificity or true anti-HBc [22], [23]. These samples called “anti-HBc only” may originate either from recovered infections having lost detectable anti-HBs or from late stage chronic infections having lost detectable HBsAg. Evidence of a secondary anti-HBs response after a single dose of HBV vaccine indicated that a large proportion of anti-HBc-only donors had indeed recovered from the infection indicated by activable memory B cells [24], [25]. The issue was further complicated by detecting low levels of HBV DNA not only in anti-HBc only donations but also in some units carrying low-level anti-HBs.

In donor populations with low prevalence of anti-HBc, deferring all reactive donors was considered affordable in terms of donation loss and more economical than introducing anti-HBs testing to differentiate between presumably non-infectious (anti-HBs ⩾100IU/L) and potentially infectious donations (no anti-HBs or anti-HBs <100IU/L). This strategy was not defendable in areas of higher prevalence where deferring anti-HBc reactive units affected negatively the blood supply too severely and at a non-affordable cost. The strategies left open to these areas were either a serologic testing algorithm with anti-HBc followed by anti-HBs or implementation of highly sensitive HBV DNA screening. The latter was adopted in affluent countries in Mediterranean Europe and Poland as well as in Singapore, Hong Kong, Taiwan and Thailand in Eastern Asia or in South Africa [19], [26], [27], [28], [29], [30]. In less affluent areas, the debate remains open.

2.3. HBV nucleic acid testing (NAT) 

In the past five years, HBV DNA detection assays that combined simultaneous detection of human immunodeficiency virus RNA, hepatitis C virus RNA, and HBV DNA (“multiplex” NAT assays) and corresponding automated testing platforms have made HBV NAT blood screening feasible. Commercial assays based on PCR (Cobas TaqScreen multiplex test; Roche Molecular System) and on TMA (Procleix® Ultrio™ Assay; Novartis/Chiron Blood Testing) showed specificity of 99.9% and 99.8%, and sensitivity of ∼8IU/mL (∼40geq/mL) and ∼12IU/mL (∼60geq/mL), respectively [4], [28]. Such high sensitivity allows HBV NAT to significantly reduce the WP left by the most sensitive HBsAg tests. However, the ability of NAT to reduce the WP depends not only on the sensitivity of both the molecular and serological tests, but also on the sample volume (200 or 500μl) as well as the dilution factor introduced by pooling samples [4], [31], [32], [33], [34]. Comparing seven HBsAg assays and seven NAT assays (three individual donor [ID] NAT and four minipool [MP] of 16 or 24 donors NAT tests) on acute-phase seroconversion panels, Biswas and colleagues showed that MP NAT and ID NAT reduced the HBV WP by 9–11 days and 25–36 days, respectively, compared to currently licensed HBsAg tests [4]. This leaves a WP of 40–50 days and 15–34 days with MP and ID HBV NAT, respectively.

Beyond shortening the WP, NAT screening, particularly in individual units, has uncovered a relatively large number of HBsAg-negative “occult” HBV infection or carriage [2], [3]. On the basis of the HBV antibody profile, OBI may be stratified into seropositive OBI (anti-HBc and/or anti-HBs positive) and seronegative OBI (anti-HBc and anti-HBs-negative) [35]. Potential biological explanations for seropositive OBI include the chronic carrier state in which HBsAg has declined over years to a sub-detectable level. OBIs are mainly found in older donors, nearly 100% carry anti-HBc, and approximately 50% also carry anti-HBs suggesting that OBIs occur largely in individuals having recovered from the infection but unable to develop a totally effective immune control [36]. Finally, mutations in the HBV genome affecting viral replication, S antigen production or detection may account for OBI [13], [37], [38].

Seronegative or primary OBIs might have either progressively lost HBV-specific antibodies or are antibody-negative from the beginning of the infection. In the absence of systematic DNA screening and follow-up investigations in seronegative individuals, very limited data support primary occult carriage and the true frequency of this condition remains unknown. One case was identified in a look-back study for post-transfusion hepatitis B [39]. Recently, Manzini and colleagues reported a blood donor who tested HBV NAT positive but did not develop detectable HBsAg over a period of 97 days despite anti-HBc and anti-HBs seroconversion [40]. Three cases of OBI in the acute stage have been reported from the Japanese Red Cross but viral loads were >104copies/mL (≳103IU/mL) and S escape mutants could not be ruled out in one of the donors [41].

OBIs are usually characterized by very low HBV DNA load in plasma (<200IU/mL). Consequently, the occurrence of viremia that is near the assay detection limit and the potential for fluctuating HBV viremia in chronically infected persons suggest that some donors with ongoing HBV infection would not be detected using highly sensitive NAT in very small pools (<10plasmas) or even in individual units [4], [26], [31], [40], [42], [43]. This was demonstrated in Japan when NAT was negative in pools of 50 plasmas but positive in pools of 20 [44]. The apparently marginal benefit of MP NAT, the high cost of ID NAT testing and its very low quality-adjusted-life-year benefit estimate have raised questions about the cost-effectiveness of HBV NAT implementation in low prevalence countries [43], [45]. These arguments do not apply in countries with higher HBV prevalence [8], [46]. It is unlikely that HBV NAT will replace current serological testing studies since up to 15% of HBsAg-confirmed-positive anti-HBc-positive donations test negative for HBV DNA even by ID-NAT [10], [19], [47].

2.4. Additional developments to potentially reduce HBV transfusion transmission 

Viral inactivation methods and large-scale HBV vaccination programs have the potential to reduce HBV transfusion transmission. Viral inactivation technologies are applied to plasma and platelet concentrates but still need development to be applied to red cell components or whole blood. A decrease of HBV infection incidence was observed following HBV vaccine implementation in many countries with moderate/high HBV endemicity [48], [49], [50]. However, it may take many years to decrease HBV prevalence among blood donors as the vaccine is usually given to newborns, but also in some programs to adolescents and at-risk health-care workers. Pereira and colleagues reported the disappearance of HBV DNA in the serum of patients with OBI after immunization with an HBsAg vaccine; the durability of the response could not be ascertained [51]. Vaccination however may favour the development of escape mutants. Anti-HBs in vaccinated people become undetectable over time and they are susceptible to HBV infection, and up to 5% of vaccinated individuals do not respond [52].

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3. Estimation of HBV residual transfusion transmission risk 

The risk of transfusion-transmitted infections has been widely estimated by using the incidence-window period model [53]. This model estimates the risk by multiplying the incidence of new infection by the average time interval during which a newly infected donor is capable of transmitting the infection [54]. However, the length of the WP varies considerably depending on the screening strategy as discussed above, and whether all WP donations are considered infectious or whether the “eclipse” phase preceding the ramp-up phase is considered infectious. Recently, Busch and colleagues proposed a modified residual risk model using an infectious WP of 38.3 days derived from a HBV doubling time of 2.6 days and assuming that one infused HBV copy will cause infection [55]. The second critical parameter is the incidence of infection that is directly measured as the number of newly infected (seroconverting) donors divided by the observed person-years at risk. This applies only to repeat donors who made more than one donation during the study period, and it may underestimate the risk as first time donors might be at greater risk of infection than repeat donors [56]. The most common approach is to measure seroconversion to HBsAg despite the rapid disappearance of this marker in a few months after infection in 95% of immunocompetent adults [41]. Therefore, a newly infected donor would not be identified as such if HBsAg is cleared from the blood between donations and true HBV infection incidence will be underestimated. To resolve this issue, an adjustment factor was calculated [57]. Different adjustment factors apply to different donor populations, and prevalence might not accurately reflect the incidence of transfusion-transmissible viral infection. Other influencing factors such as test or process errors, mutant viruses that are not detected by blood donation screening, and OBI are not considered in the model [58]. Residual risk estimates reported from different countries are summarized in Table 1. Data comparison should be undertaken with caution since some of the listed countries perform anti-HBc testing in the whole donor population or in particular subsets of donors. In countries not performing anti-HBc testing, seropositive-OBI donors represent a substantial increment in the transfusion transmission risk. Despite all these limitations, the residual risk estimates provided seem to have some validity as they tend to parallel the rates of HBV endemicity. The residual risk per million donations is 0.69–8.69, 7.5–15.8, and 30.6–200 in areas of low, moderate, and high endemicity, respectively (Table 1).

Table 1. Estimated residual risk of transfusion-transmitted HBV infection (per million donations from repeat donors).
CountryHBV endemicityHBV RR without HBV NATAnti-HBc screeningReferences
EnglandLow1.66No[59]
BelgiumLow5.0Yes/noa[53]
FranceLow0.69Yes[60]
The NetherlandsLow2.1No[53]
FinlandLow2.04No[53]
GermanyLow4.35Yes/nob[61]
SwitzerlandLow8.69No[62]
CanadaLow6.55Yesc[63]
USALow2.05–4.88Yes[64], [65]
AustraliaLow0.75Yes/nod[66]
GreeceModerate7.5No[53]
ItalyModerate13.9–15. 8No[53], [67]
SpainModerate9.78No[68]
ChinaHigh30.6–57.1No[69]
Hong KongHigh200No[53]

aAnti-HBc screening in first-time blood donors.

bLimited anti-HBc screening on a voluntary basis.

cAnti-HBc screening implemented in 2005.

dAnti-HBc screening in donors with a history of hepatitis.

The incidence of anti-HBc seroconversion has been proposed as a modifier of the WP-based model resulting in a reduction of risk from 0.69 to 0.49 [60]. This adjustment appears legitimate but its reliability highly depends on the criteria used to identify anti-HBc seroconversion [70]. Measuring the incidence of anti-HBc seroconversion may overestimate the HBV infection incidence related to the poor specificity of anti-HBc assays and the lack of confirmatory assays [71]. Laperche and colleagues proposed to support anti-HBc incidence by the concomitant detection of anti-HBe, anti-HBs in the absence of vaccination, and HBV DNA when implemented. Recent data obtained in European blood donors indicates that HBV DNA-positive/anti-HBc-positive without anti-HBe is as or more frequent than associated with anti-HBe [26], [71], [72], [73].

Another method proposes to calculate the incident infection rate as the number of NAT-yield donations divided by the number of person-years [54], [55], [63]. This method allows the determination of the incidence rate in all donations, and occult HBV carriage will be included in the calculation of the residual risk. This method highly depends on the accuracy of the estimation of HBV NAT yield. Indeed, HBV DNA yield appears directly related not only to the analytical sensitivity and pool size of the HBV NAT assay, but also to the analytical sensitivity of the HBsAg used for screening and to the general HBV prevalence in the donor population. HBV NAT yields reported from countries with low, moderate, and high HBsAg prevalence range between 1:4000 and 1:730,000 [22], [65], [72], [74], [75], [76], [77], 1:4000 and 1:20,300 [26], [27], [78], [79], [80], and 1:192 and 1:5200 [8], [10], [19], [28], [29], [30], [81], respectively. As studies conducted in different countries used different serological and NAT assays with variable pool sizes, and were performed in selected (repeat, first time, or anti-HBc-positive donors) or unselected populations of blood donors, comparison of results is difficult. Despite these limitations, HBV DNA yield increases with HBsAg and anti-HBc prevalence, irrespective of MP- or ID-NAT screening or anti-HBc status [82], [83]. In low-prevalence Germany, implementation of HBV NAT (essentially in-house assay) in pool of 96 submitted to prolonged high-speed centrifugation or individual unit resulted in residual risks of 1.61 and 1.23 per million donations, respectively, compared to 4.35 per million without NAT [61]. Similarly, a study conducted in high-prevalence China showed that a residual risk of 30.6 per million donations after HBsAg screening was reduced to 29.0 and 17.4 when NAT was used in pools of 16 and in individual testing, respectively [69].

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4. HBV transmission by transfusion 

4.1. Determining the HBV infectious dose(s) 

The estimated residual risk of HBV transfusion transmission remains significantly higher than the risk of either HIV-1 or HCV. Whether residual risk estimates translate into true rate of infection is largely unknown since estimates are generally based on the simplification that all HBV DNA-containing donations are infectious.

Studies have attempted to address this question by using the chimpanzee model. Genotype A or genotype C inoculum derived from two infected blood donors who were in the pre-acute phase (HBsAg and HBV DNA-positive but anti-HBc-negative) were used to infect two chimpanzees whose pre-acute phase serum samples were then used to infect two other chimpanzees. The estimated minimum HBV copy numbers that could infect 50% of the chimpanzees (CID50) was approximately 10 copies or geq, irrespective of HBV genotype [84]. A similar result was reported from three chimpanzees infected with serum from a HBV genotype A-infected individual in the acute phase of infection [44]. Using three serum inoculae from chronic carriers (HBsAg-positive and anti-HBc-positive), Hsia and colleagues estimated CID50 was 169 geq for genotype A, 3 for genotype C, and 78 for genotype D [85]. Utilizing a chimeric mouse model tolerating human liver tissue, Japanese investigators determined the HBV infectious dose of a pre-acute and late acute HBV serum required for transmission to be 10 and 100 geq, respectively [86], [87].

In humans, HBV transmission was reported from donors in the WP and OBI donors showing HBV DNA load <20IU/mL (Table 2) [42], [88], [89]. However, in some cases, units from WP and OBI donors were not infectious even though viral load ranging between <20 and >500IU/mL (<100 and >2500geq/ml) was transfused [31], [88], [89], [90]. The lack of clear relationship between infectivity and viral load in blood components may be related to immune factors affecting the susceptibility to infection in recipients as discussed below. In addition, HBV infectivity is essentially related to the amount of plasma transfused and the viral load in the product. At equal volume of product, fresh-frozen plasma (FFP) and platelet concentrates (PC) suspended in plasma were 3- to 20-fold more infectious than red cell concentrates containing approximately 20% of plasma.

Table 2. Transfusion transmission of HBV from HBsAg-negative blood donations.a
ReferenceDonorsProducts transfusedcTransmission casesRecipients anti-HBs (IU/L)
Anti-HBcHBV DNA (IU/mL)Anti-HBs (IU/L)bHBV statusNb recipientsNb transmission
[94]Neg.Weak pos. WPPC11NAe
RBC11NA
FFP11NA

[31]Neg.660 WPPlasma11NA
RBC10NA
Neg.Neg. WPPC11NA
Neg.600 WPPC11NA
Neg.160 WPPlasma11NA
Neg.>10 WPNA11NA
Neg.>10 WPNA11NA
Neg.>10 WPNA11NA
Pos.>10NAOBINA11NA
Pos.>10NAOBINA11NA

[42]Neg.<25 WPRBC11NA
PC11NA

[93]Neg.Pos. WP 11NA
Neg.Pos. WP 11NA
Neg.Pos. WP 11NA
Neg.Neg. WP 1NA

[90]Pos.10–100Neg.OBINA112NA

[95]Pos.<10–260Pos.OBIRBC90NA
(2 534–7 371) FFP20NA

[88]Weak<10–40Neg.OBIPC106NA
Pos. NA

[96]Pos.<10Pos.OBIdPC650NA

[89]1 Pos.<20Neg.OBIFFP11NA
32 Pos.<20–2411 PosOBI17 RBC320NA
12 Neg. 14 FFP, 1 NA
9 Und. PC NA
11Neg.<20–76 WP5 RBC, 41111NA
FFP, 2 PC NA
11Neg.<20–60 WP5 RBC, 4110NA
FFP, 2 PC NA

[97]Pos.180Pos. (12)OBIFFP11Neg.
RBC11Neg.
<1–63Pos. NA20Neg.
(15–29)
[98]Neg.>500 WPRBC11Pos.
PC10(12–65)
Pos.
(15)

[99]Neg.171 WPPC11Neg.
10Pos. (135)
1252 11Neg.
10Pos. (164)

aOnly confirmed HBV transfusion-associated transmission were considered.

b1 International Unit (IU) is equivalent to approximately 5 genome equivalents (geq) or copies for HBV genotype A, subtype adw2.

cRBC, red blood cells; FFP, fresh-frozen plasmas; PC, platelet concentrates.

dBreakthrough of an escape mutant.

eNA, not available.

4.2. Risk of transmission from clinical data 

While HBV transmission from HBsAg-negative donations is supported by several studies since the early 1980s [91], it is not a frequently reported event, at least in low-prevalence countries, consistent with the small number of WP and occult carriage reported. In the United States, the risk of transfusing a potentially infectious HBsAg-negative/anti-HBc-positive/HBV DNA-positive unit has been reported to be ∼1 in 50,000 donations if all HBV-positive donations were assumed to be infectious [23], [65]. However, of 7381 cases of acute hepatitis B reported in 2003, 49 were initially reported as transfusion-associated. Only 10 of those were further confirmed by the Centers for Disease Control and Prevention as acute cases of hepatitis B involving transfused blood products and finally only 1 case could be associated with a single infected donor [92]. Similar data were reported from Canada, the UK, and Japan [75], [89], [93].

Data summarized in Table 2 indicate that (1) WP and anti-HBs-positive and negative OBI units can transmit HBV; (2) the confirmed HBV transmission rate of WP-derived donations is higher than by occult carriers (81% versus 19%) but may be biased by the large number of Japanese cases identified with a peculiar set of anti-HBc and DNA screening protocol [89]; (3) viral transmission can be associated with extremely low level of HBV DNA in anti-HBc-positive-only units (<20IU/mL) or blood collected during the very early phase of acute infection (eclipse phase) in which neither HBsAg nor HBV DNA is detectable [31], [93]; (4) HBV DNA load is similar in infectious and non-infectious anti-HBc-positive donations, suggesting that viral load is not the only factor for infectivity; and (5) the presence of anti-HBs seems to largely protect from transmission [89], [100], except in rare cases [97] (Fig. 1).

  • View full-size image.
  • Fig. 1. 

    Relationship between HBV DNA load and anti-HBs reactivity in an OBI donor associated with transfusion transmission of HBV (modified from [97]). Open and plain circles indicate anti-HBs reactivity (IU/L) and HBV DNA load (IU/mL), respectively. The dashed line indicates absence of HBV DNA testing. HBV transmission is indicated by black vertical arrows; absence of transmission by an open arrow.

The concomitant presence of anti-HBs with HBV virions in the peripheral blood of donors neutralizes in proportion of antibody titer and ability to recognize surface protein antigens. Experiments in chimpanzees showed no HBV infection in animals transfused with blood from three anti-HBs-positive human plasmas, despite exposure to an HBV DNA dose known to be infectious in the absence of anti-HBs [101]. The presence of anti-HBs following natural infection, vaccination, or passive immunoprophylaxis prevents de novo HBV infection in transplanted patients receiving anti-HBc-positive livers [102], [103], [104], [105]. Consequently, the transfusion of anti-HBc-positive blood with high levels of anti-HBs (>200IU/L) is allowed in Japan and no post-transfusion cases have been documented from such units [31], [32], [89]. Dreier and colleagues reported intermittent low HBV DNA levels (<10–260IU/mL) over a 7-year period in an HBsAg-negative anti-HBc-positive donor with anti-HBs (>2000IU/L) but no HBV transmission occurred [95]. Another study described a breakthrough HBV escape variant in a plateletpheresis donor [96]. Infection occurred three years after vaccination, the donor developed a persistent low-level HBV-infection (HBsAg-negative, anti-HBc-positive, HBV DNA at levels <5IU/mL) despite a high vaccine-induced anti-HBs response (>1000IU/L). Lookback of 65 recipients of PC from this donor (∼200IU/donation) did not reveal HBV transmission.

The principle of protection by units with high levels of anti-HBs is commonly accepted, although there is no agreement on the threshold level but 100IU/L is often cited [106]. No evidence of transmission was found in 131 recipients who were transfused with 97 components containing anti-HBc and anti-HBs at levels <100IU/L [107]. In contrast, others described five cases of HBV transmission presumably linked to anti-HBc-positive donors: three lacked anti-HBs and two had low level of anti-HBs (probably <10IU/L) [23], [108]. Recently, one case of an OBI donor with anti-HBs who transmitted to two immunocompetent transfusion recipients of FFP and red blood cells (RBC) was reported [97]. The implicated donation contained anti-HBc, anti-HBs (12IU/L), and 180IU/mL of HBV DNA. Previous donations contained 6–10 times less viral DNA than the index donation, anti-HBs levels ranged between 15 and 29IU/L, and no clinical evidence of HBV transmission was recorded in 14 recipients. It was speculated that the main factor for infectivity was a temporary higher viral load sufficient to overcome the relatively weak neutralizing capacity of a low anti-HBs level. This interpretation was supported by a secondary anti-HBs immune response. This particular case clearly illustrates that the neutralizing capacity of low-level anti-HBs is limited and reinforces the validity of considering anti-HBs below 50–100IU/L to be poorly protective from infectivity when HBV DNA is present. This factor needs to be considered in triggers to maintain effective post-vaccination protection [50], [109], [110], [111], [112].

The immune status of the recipient is another critical factor in transfusion transmission of HBV. After acute HBV infection was diagnosed in a regular apheresis donor, four platelet components recipients were identified; two HBV-naı¨ve were infected but two who were anti-HBs-positive pre-transfusion (135 and 164IU/L) were not. Several studies indicated that recipients of anti-HBc-positive organs (e.g. liver) developed HBV infection, even if HBV DNA was not detected in the donors’ serum [113], [114], [115], [116]. These data suggest an increased susceptibility to HBV infection of transplant patients undergoing intensive immunosuppressive therapy in the absence of prophylactic treatment. This situation can be probably derived from organs to blood components as approximately 50% of recipients of blood components in Western Europe present some degree of immunodeficiency [117]. It was shown that both active and passive neutralizing anti-HBs likely delayed but did not prevent acute infection when the immune system was impaired [98].

4.3. Diagnosis of transfusion-transmitted HBV 

Transfusion transmission can be documented by (1) notifying and testing donors that have been implicated in a case of possible post-transfusion hepatitis B (traceback); (2) notifying and testing recipients after the administration of potentially infectious HBV-containing blood products (lookback); and (3) prospective testing of donor–recipient pairs. Each strategy has its own limitations. No prospective studies have been conducted so far because it requires an extremely large number of patients and high cost.

The traceback strategy relies primarily on clinical evidence and proper diagnostic of hepatitis B in the recipient. Inaba and colleagues reported three of four cases of acute hepatitis B and two suspected seroconversions that were not recognized by local physicians as being related to transfusion [88]. Twenty UK cases of hepatitis B associated with presumably infectious donors were identified (but only four were confirmed) over the past 15 years, none of which were suspected by local physicians in a timely fashion [93]. Clinical data suggest that only 20–35% of recipients will be symptomatic, and the length of the incubation period before symptoms develop can extend up to 6 months, irrespective of the amount of virus transfused [3], [31]. HBV incubation time can be considerably prolonged (up to 13 months) in unusual circumstances involving an impaired immune system and active or passive neutralizing antibodies to HBV in the recipient [98], [100]. There is preliminary evidence that immunocompromised patients are not only more susceptible to lower infectious dose including in the presence of anti-HBs but also at higher risk of developing chronic infection [105]. The ∼50% mortality rate within 6–12 months post-transfusion reported in transfusion recipients may also limit identification of HBV transmission [118].

Lookback of recipients who were transfused with donations from a newly identified HBV-infected repeat donor is often used to identify recipients at risk of HBV transfusion transmission [118]. Evidence of transfusion transmission of HBV may not be obtained because pre-transfusion samples are rarely available, HBV infections might have resolved before they are identified by lookback, and often recipients cannot be traced or samples obtained [63]. As HBV marker levels may fluctuate over time [47], [88], follow-up of suspected donors and testing of archived samples are necessary to exclude recent infection and false-positive [106], [107], [119]. Testing for archived donations and recipient samples requires access to a frozen repository of donor/recipient samples. Such system exists in several national blood services [31], [89], [120].

Post-transfusion hepatitis B is not necessarily transfusion-transmitted and iatrogenic sources of infection should be systematically investigated before concluding that HBV-infected blood donors are involved in viral transmission [109], [121], [122]. In a systematic investigation of suspected transfusion-transmitted HBV infections, Matsumoto and colleagues showed that the majority of reported cases could not be linked to laboratory testing of transfused blood [31]. Caution should be exercised in concluding that a suspected transfusion-transmitted case is causally related to transfusion, unless other iatrogenic sources of infection have been eliminated, adequate donor follow-up and laboratory testing have been performed, and more importantly, pre- and post-transfusion testing of recipients has been completed. Unfortunately, pre-transfusion testing of the recipient is missing in many studies making difficult to establish if the investigated recipient was infected before or after transfusion [63], [100], [109]. In addition, HBV reactivation has been largely documented in immunocompromised individuals with past history of hepatitis [123 for review]. Dependent on the degree of T-cell depletion, the risk of reactivation varies, low as demonstrated in kidney transplant recipients, or high in liver transplant recipients or patients treated for graft-versus-host disease or undergoing allogeneic bone marrow or stem cell transplantation or treatment with aggressive chemotherapy or monoclonal antibodies against T- or B-cells. In the latter groups, close monitoring of HBV DNA for anti-HBc-positive recipients or systematic treatment with antiviral drugs (i.e. lamivudine) have been advocated [123]. Definitive evidence of transfusion transmission can be obtained by genomic analysis of the viral strains present in both donor and recipient.

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5. Conclusions 

Despite continuous technical improvement in blood donation screening, hepatitis B infection remains a major risk of transfusion-transmitted viral infection. The residual risk of HBV transmission is related to the pre-seroconversion window period, infection with immunovariant viruses, and with occult carriage of HBV. Reduction of HBV residual risk is achieved by developing more sensitive HBsAg tests, by adopting anti-HBc screening if appropriate, and recently by implementing HBV nucleic acid testing, either in minipools or more efficiently in individual samples. Compared to serological testing, HBV NAT combines the ability to significantly reduce the window period and to detect occult HBV carriage. HBV NAT yield in HBsAg-negative blood donations was studied in low-, moderate-, and high-endemic areas in pools and individual plasmas. Anti-HBc screening has the potential of excluding the majority of OBIs, leaving only the rare cases of primary OBI or of escape mutant associated with anti-HBs alone. However, it does not detect pre-seroconversion window period infections, and is not practical in areas with anti-HBc prevalence >5% where too many donor deferrals would negatively impact the blood supply. Based on available data, NAT is the only theoretical choice to reduce HBV risk in high-endemic countries. However, most of these countries do not have access to and could not afford such technology. Alternatives to simplify methods and to reduce NAT cost should be investigated.

The development of HBV NAT assays substantiated decades of clinical observation that HBsAg-negative/anti-HBc-positive blood could transmit HBV. For the transfusion community, the remaining critical question is: are blood components from OBI donations infectious by transfusion? Clinical observations suggest limited transmission rate compared to WP yield cases. Low transmission rate may be related to the low viral loads generally observed in OBIs (even if the HBV infectious dose by transfusion is still unknown) or to the presence of defective variants associated with occult carriage. OBIs carrying detectable anti-HBs (∼50%) are essentially not infectious by transfusion. However, recent data suggest that the neutralizing capacity of low anti-HBs may be inefficient when overcome by exposure to high viral load. Anti-HBc blood units without detectable anti-HBs appear moderately infectious except in immunocompromised recipients. Immunodeficient elderly and patients receiving immunosuppressive treatments (organ transplantation or cancer chemotherapy) may be susceptible to infection with lower infectious dose even in the presence of anti-HBs. The immune status of blood recipients should be taken into consideration when investigating “post-transfusion” HBV infection. Pre-transfusion testing and post-transfusion long-term follow-up of recipients, and molecular analysis of the virus infecting both donor and recipient appear essential to definitively confirm transfusion transmission of HBV.

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☆ The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

PII: S0168-8278(09)00391-2

doi:10.1016/j.jhep.2009.05.020

Journal of Hepatology
Volume 51, Issue 4 , Pages 798-809, October 2009

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