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Vox Sanguinis (2011) 100, 92–98 ª 2010 The Author(s) Vox Sanguinis ª 2010 International Society of Blood Transfusion DOI: 10.1111/j.1423-0410.2010.01426.x REVIEW Hepatitis B, hepatitis C and HIV transfusion-transmitted infections in the 21st century D. M. Dwyre, L. P. Fernando & P. V. Holland Department of Pathology, University of California Davis Medical Center, Sacramento, CA, USA Received: 15 July 2010, revised 22 September 2010, accepted 25 September 2010 In the past, transfusion-transmitted virus (TTV) infections were not uncommon. In recent years with advanced technologies and improved donor screening, the risk of viral transfusion transmission has been markedly reduced. Hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have all shown marked reduction in transmission rates. However, the newer technologies, including nucleic acid technology (NAT) testing, have affected the residual rates differently for these virally transmitted diseases. Zero risk, which has been the goal, has yet to be achieved. False negatives still persist, and transmissions of these viruses still occur, although rarely. It is known that HBV serological testing misses some infected units; likewise, HBV NAT–negative units have also been known to transmit the virus. Similarly, HIV minipool NAT–negative units have transmitted HIV, as recently as 2007; likely, these transmissions would have been prevented with single-unit NAT testing. Newer technologies, such as pathogen inactivation (PI), will (ideally) eliminate these falsely test negative components, regardless of the original testing method used for detecting the viruses. Key words: hepatitis B, hepatitis C, HIV, pathogen inactivation, transfusiontransmitted infections. Introduction The first cases of transmission of a viral illness through blood transfusion were reported in 1943 [1]. Laboratory testing for viral transfusion-transmitted viruses began in 1969 with testing for hepatitis B surface antigen (HBsAg). To reduce the risks of transmission of other viral illnesses (e.g. non-A, non-B viral hepatitis), introduction of alanine aminotransferase (ALT) testing and antibody to hepatitis B core antigen (anti-HBc) testing began in the 1980s [2]. More specific disease serological testing (anti-Hepatitis C virus antibody and HIV antigen and antibody testing) followed in the 1980s–1990s markedly reducing the risk of these transfusion-transmitted viruses (TTV). With the implementation of nucleic acid technology (NAT) in 1999, there was further reduction in viral infections transmitted by blood transfusion. Using serological Correspondence: Denis M. Dwyre, Department of Pathology, University of California Davis Medical Center, 4400 V Street, Sacramento, CA 95817, USA E-mail: [email protected] 92 methods, the risk of Hepatitis B virus (HBV) is currently estimated to be 1 in 282 000 to 1 in 357 000 with a ‘window period’ (time from infection to first reactive test) of 30–38 days [3]. The current risk of transfusiontransmitted Hepatitis C virus (HCV) infection with NAT testing in place along with serologic testing is estimated to be 0Æ03–0Æ5 in 1 000 000 units [1]. For human immunodeficiency virus (HIV), transmission risk using NAT and serologic testing is currently estimated to be 1 in 1Æ5 million to 1 in 4Æ3 million [4,5]. Although quite small today, the risks for transfusion transmission of HBV, HCV and HIV persist. So, efforts to reduce the risks to zero continue. Hepatitis B After the discovery of widespread HBV infection became evident in 1963 with the introduction of HBsAg testing, HBV was noted to have a high prevalence in multiply transfused patients. However, it is now known that HBV is a very common infection in the general population and that transfusion transmission accounts for a minority of those Transfusion transmission of hepatitis B, hepatitis C, and HIV 93 infections. The prevalence of HBV differs by geography. With over 300 million carriers of HBV worldwide, the infection, as measured by HBV surface antigen (HBsAg) positivity, remains endemically high in Africa, parts of Asia, the Middle East and parts of South America, ranging from 8% to 15% of those populations. In low prevalence areas, such as the United States, western and northern Europe, Canada and parts of South America, the prevalence is estimated to be < 2% [1]. Acute infection with HBV, whether transmitted via transfusion, intravenous drug use, perinatally or via sexual contact, may be asymptomatic or cause clinical viral hepatitis with nonspecific constitutional symptoms, including jaundice. Rarely, acute infections, including acute infections from transfusion-transmitted HBV, can cause fulminant liver failure and death [6]. After transmission of HBV, HBV DNA is the first marker to be present in the blood. After viral replication in the liver, HBV viral load can attain 108–1010 viral particles per millilitres of serum [1]. Viremia during the window period, however, is exponentially lower; infectivity, incidentally, in also lower in the WP, most likely related to antibodies (anti-HBc and anti-HBs) formed after acute infection [7]. Testing for those infected with HBV historically involves detection of HBsAg. HBsAg is present in the serum of infected individuals from weeks to months after onset of infection and before symptoms begin. Some infected individuals never test positive for HBsAg, but generally will produce an antibody response to Hepatitis B core antigen (HBcAg): anti-HBc. The fact that there are some false-negative tests for HBsAg is the reason for testing for anti-HBc in some countries. However, determination of HBsAg-negative ⁄ anti-HBc-positive distant HBV infections in individuals, such as healthy blood donors without a history of hepatitis, testing falsely positive for anti-HBc has been a persistent problem for blood donor collection facilities. Generally, two positive anti-HBc tests will result in permanent deferral from donating blood in the United States. Recently, however, an algorithm for re-entry of these donors has been approved by the US Food and Drug Administration (F.D.A.) [8]. Unlike HCV and HIV testing, NAT HBV DNA testing has not eliminated the necessity for serological testing for HBV carrier donors. Where instituted, it was hoped that NAT testing for HBV would 1) reduce the window period for HBV, 2) identify low-level carriers of HBV, 3) provide another mechanism for re-entry of HBsAg false-positive donors and 4) ultimately replace serological testing. NAT testing for HBV DNA has been implemented to a variable extent in industrialized countries in Europe, North America, Asia, Australia and Africa. Occult HBV infections (HBsAg negative, HBV NAT positive) have been identified in all studies, in the range of 1 ⁄ 2000–1 ⁄ 107 000 [9]. Japan was in the higher part of the range with the difference possibly being related to the use of larger pools for their NAT testing [9]. It has been shown that occult HBV infections can transmit the virus via blood transfusions, but the infectivity is not 100% [10], and the level of viremia needed to infect has not been determined in humans. However, in chimpanzees, it may be related to HBV genotype [11]. NAT testing for HBV varies by country and varies by blood centre within countries. HBV NAT testing is mandated in some countries [12]. Single-unit NAT testing can detect very low levels of HBV DNA (< 100 IU ⁄ ml). With the availability of multiplex testing of small pools of donor sera, more blood centres are implementing HBV NAT, along with HCV and HIV. However, without single-unit NAT HBV DNA testing, the window period may not be shortened that much, compared to the sensitive tests available today for HBsAg (like PRISM ⁄ Abbott Park, IL, USA). This can be explained by the relatively slower doubling time of HBV in the window period, resulting in a lower viral load. Thus far the consensus is that NAT should be used in conjunction with serological testing to identify low-level infections as well as infections that are at the ends of the window periods of detection. There is no consensus either on whether single-donor NAT or what size pool NAT is optimal, and it may depend on the prevalence of HBV in the country. Additionally, HBV infectivity may depend upon the immunosuppressive state of the recipient of the blood component. Infectious disease testing on donated blood is of great importance in the reduction in risk for TT HBV infection. Other processes may also reduce the risk of HBV from blood components. For example, optimization of donor screening pre-donation is where most of the potential infected donors can be eliminated from the donor pool. This screening process could and should be individualized by country and even community. On the other end of the process, postdonation, pathogen inactivation (PI) may be almost 100% effective in eliminating the risk of HBV TTD from platelets and plasma in countries where it has been implemented. The role of effective testing remains critical, at this time, because of the lack of availability of PI for red blood cell components and whole blood. Finally, the role of vaccination for HBV also has the potential of almost completely eliminating the potential risk of HBV by blood transfusion; the reduction in risk that widespread vaccination can provide would be large in countries where the virus is endemic and access to vaccinations is currently limited. Hepatitis C After the discovery of hepatitis A virus (HAV) and HBV, a significant number of patients testing negative for HAV and HBV and with clinical presentation or laboratory evidence of viral hepatitis were identified; these patients were 2010 The Author(s) Vox Sanguinis 2010 International Society of Blood Transfusion, Vox Sanguinis (2011) 100, 92–98 94 D. M. Dwyre et al. presumed infected with what was initially termed non-A, non-B (NANB) viral hepatitis. Most of these NANB viral hepatitis patients had a history of intravenous drug use. The majority of patients with NANB hepatitis later tested positive for HCV after testing for anti-HCV became widespread in the 1990s. After testing was available, it was also verified that blood transfusion was another significant mode of transmission of HCV. The infection is present worldwide with lower incidence rates in North America, Australia and Europe (approximately 2%) and a higher rate in Egypt (> 5%). Once infected with HCV, the virus travels via the blood to the liver where it replicates. Viremia occurs usually with few symptoms. Similar to HBV, fulminant lethal acute HCV infection can occur rarely. More typically, patients do not clear the virus on their own, so HCV develops into a chronic hepatitis and the patients become chronic carriers of the virus. Because many HCV infections are asymptomatic in the acute setting, the diagnosis is often made during the chronic phase. After exposure to HCV, usually parenterally, Hepatitis C antigen is present initially, then anti-HCV develops in the weeks following infection. The specific diagnosis of HCV infection requires serological and ⁄ or molecular-based (NAT) assays. In rare instances, anti-HCV may not develop; in these cases, a definitive diagnosis of HCV requires molecular-based (NAT) assays. Spontaneous recovery from HCV infection occurs in 15–45% of infected individuals with recovery in the higher range occurring in women given anti-D immunoglobulin contaminated with HCV [13,14]. NAT of plasma intended for fractionation and of blood donations for HCV RNA began in the late 1990s when methodologies became available. NAT for HCV is now required in many countries. As anti-HCV testing is also generally performed in addition to NAT, infected units from donors with spontaneous recovery from HCV would also be eliminated from the blood supply. Further reduction in transfusion-transmitted HCV, as well as any TTV, begins with improved donor screening. Recent data from the American Red Cross have shown that HCV positivity in blood donors has increased from a rate of 1Æ96 ⁄ 100 000 to 2Æ98 ⁄ 100 000 from 2005 to 2008. The increase has been primarily in Caucasian donors, especially in those donors over 50 years of age [4]. Donor screening, i.e. focusing donor questions on risk factors and on certain racial ⁄ age populations may aid in eliminating potentially infected donors prior to donation. A major risk factor identified in population screening is sharing of needles, especially in use of drugs, as well as reuse of non-sterilized needles. Having had surgery in a developing country (with unknown exposure to one of the blood) may be a risk factor as noted in a study from Mexico where risk factors to HCV infection was noted to be having had surgery or a prior blood transfusion [15]. It is known that there are presumed false-positive HCV donors (anti-HCV positive, HCV NAT negative). With further complex methods evaluating for immunological response to HCV (not ready for routine screening testing) [16–18], it is known that some of these donors are truly negative, some of those negative because of seasonal viral infections [19] and some of the donors being positive having recovered from the infection. However, it is not believed that these positive donations are capable of transmitting HCV. Unsafe endoscopy practices at a US endoscopic clinic may have exposed patients to viral infections [20]. In the absence of other risk factors, these patients would not have been identified as higher risk for HCV in donor screening. With the use of anti-HCV antibody testing only, before HCV NAT testing, the risk of transfusion transmission of HCV was reduced considerably. The window period for HCV was approximately 70 days [1]. With the introduction of NAT, the window period has been reduced to approximately 12 days [1,21]. NAT HCV testing is mandated in many industrialized countries. Combined antibody ⁄ antigen testing is available, but this combination still is not as sensitive as NAT [22]. Generally, pooled NAT testing identifies virtually all HCV-infected units because of the high levels of HCV RNA [23,24]. In a South African study, single-unit testing was performed, and only one window period HCV NAT–positive unit was identified. It should be noted that South Africa has a low incidence of HCV. In a German study, multipool NAT was used (10–96 donations per pool), and only one documented case of transfusion-transmitted HCV was missed with multipool NAT over a 5-year period. All three main genotypes were detected. Individual NAT testing may not improve upon the multipool testing; however, as noted in a case study, also from Germany, HCV was transmitted from a red cell unit that was negative by individual NAT HCV testing [21]. NAT testing has markedly improved the detection of HCV in donor units, as well as dramatically reduced the window period. However, the risk persists, albeit low. PI has been shown to virtually reduce the risk of HCV transmission to zero in vitro. This has great potential, especially in light of the fact that, unlike HBV, an effective vaccine against HCV is not available. PI is not currently universally available. PI would be of great benefit in developed countries where it could potentially reduce testing and the costs associated with testing. PI would be of greater utility in developing countries where universal testing is not available; testing for many infections would not be needed. The major limitation is that PI is only available for plasma and platelet products, and not for red blood cells. As noted in the just-mentioned case study of individual NAT failure to 2010 The Author(s) Vox Sanguinis 2010 International Society of Blood Transfusion, Vox Sanguinis (2011) 100, 92–98 Transfusion transmission of hepatitis B, hepatitis C, and HIV 95 identify a low-level case of infectious HCV, the component transmitting the HCV was a red blood cell unit. HIV In June 1981, the landmark report of five cases of Pneumocystis jiroveci (then P. carini) Pneumonia in otherwise healthy young men heralded a new disease eventually named acquired immune deficiency syndrome (AIDS) [25]. Shortly thereafter, AIDS was also reported in IV drug users and a few patients with Haemophilia. In December 1982, AIDS was diagnosed in a San Francisco baby who had received a platelet transfusion from a gay man who died of AIDS [26]. The realization that we had a new infectious agent (possibly a retrovirus) that had started to infiltrate the blood supply mobilized all blood collection agencies throughout the Western world to do everything possible to prevent potentially infected individuals from donating blood. The advent of AIDS also mobilized the research community to identify the causative agent and develop a test for it. In the United States, the first donor deferral guidelines were put in effect in January 1983. Those early efforts to indefinitely defer prospective blood donors at risk and their sexual partners helped decrease the incidence of transfusion-associated AIDS by an estimated 90% [27]. The human immunodeficiency virus (HIV) (originally named HTLV-III) was described by Gallo and Montagnier [28] in 1984, and the first ELISA antibody test was available to blood banks in April, 1985. It is estimated that in the early 80s, the risk of being infected by a blood transfusion was in the order of 1:100 in some US cities, like San Francisco [27]. The focus, as well as the public perception, of transfusion medicine was changed forever. In 2005, it was estimated by the WHO that 38 million people were living with HIV world wide, that 4Æ1 million were newly infected and 2Æ8 million had died of AIDS. The vast majority of AIDS cases were not because of transfusions, however. In sub-Saharan Africa alone 24 million people are infected. The first generation ELISA tests for anti-HIV were able to detect the great majority of asymptomatic HIV carriers, but the window period (time to seroconversion) in newly infected individuals was approximately 56 days. Second and third generation anti-HIV tests reduced the window to 33 and 22 days, respectively. The HIV P-24 antigen test was introduced in March, 1996 with the hope of further reducing the window period. Transmission of HIV involving three different donors negative for both anti-HIV and P-24 antigen testing was documented in 1986 [29], 1987 [30] and 2007 [31]. The first one was a frequent platelet donor who infected three recipients 11 and 4 days (double donation) prior to becoming HIV P24 antigen positive. Subsequent NAT testing was positive on the )4 day donation, but negative for the )11 day one. The second one involved transmission of HIV by both platelets and RBCs. NAT on the undiluted donor plasma was positive, but detection was inconsistent in the 1:16 and 1:24 dilutions (the usual pool sizes in the USA). On the third case, a retained sample from a donation 4 months earlier tested positive with individual NAT, but had tested negative on a 96 sample minipool. Following this case, individual donation (ID) NAT testing for HIV, HCV and HBV was implemented in Denmark. Minipool NAT testing for HIV and HCV was introduced in US blood collection centres in 1999, reducing the HIV window of infectivity to 11 days. Minipool NAT testing had already been implemented in some European Countries (like Germany). Five cases of HIV transmission by donations negative by NAT minipool testing have been reported in the United States from four donors [32, 33], one in Germany [5] and one in France [34]. In working up these transmissions in detail, there are several common findings: The viral load was too low to be detected by pooled testing which generally requires > 90 copies ⁄ ml. By look back, it was determined that these donors’ seroconversions were recent, thus explaining the low viral load. More important, further questioning of the involved donors revealed risk factors, specifically recent male to male sexual contact, that were denied in the original screening interview. Retesting of stored donor samples with ID NAT was reactive in the cases where it was performed. The importance of viral load is further illustrated by a report by Ferreira and Nel [35]. In January 2003, a 52-yearold male tested HIV antibody positive on his 55th blood donation to the South African National Blood Service. Look back on his earlier, HIV-negative donation from October 2002 showed that three components were made from it: RBCs, transfused 12 days after collection to a 20-year-old patient; platelets, transfused as part of a pool to a 12-year old patient 5 days after collection; and fresh frozen plasma, originally sent for fractionation but retrieved for further testing. The viral load was estimated to be only 12 copies ⁄ ml. The sample tested negative for anti-HIV and HIV p-24 antigen. It tested positive, however, by NAT. The assay used has a sensitivity between 16Æ7 and 25 copies ⁄ ml. In January 2003, the recipient of the platelet pool tested positive for HIV antibody and HIV p-24 antigen. Phylogenetic analysis of donor and recipient samples confirms the transmission from donor to recipient. The recipient of the red cells was tested for HIV antibody in March 2003 and found to be negative. Again in July 2003, he remained negative for HIV antibody, and NAT for RNA, the same test found positive in the platelet recipient. In the United States, American Red Cross’ 10 years experience (1999–2008) after NAT minipool testing was 2010 The Author(s) Vox Sanguinis 2010 International Society of Blood Transfusion, Vox Sanguinis (2011) 100, 92–98 96 D. M. Dwyre et al. implemented revealed the following: Of 66 million donations tested, mostly pools of 16, there were 32 positive HIV NAT yield samples with an incidence of 1:2 060 000. Further analysis of the data revealed some disturbing trends: While in the years 2005 ⁄ 2006, 67 incident HIV positive tests (both NAT and serology) were found, in the years 2007 ⁄ 2008 there were 92, with an increase of 25 cases. The number of 16- to 19-year-old males in both groups went from 6 to 21, a statistically significant increase (P < 0Æ01). A preponderance of non-Caucasian donors was also noted [4]. These demographics parallel the incidence of HIV in the community. While there was no suggestion of test seeking behaviour when analysing the US data, a 2006 Brazilian study showed that donors still use the blood donation process to obtain HIV testing [36]. These finding underscore the importance of the initial donor history questionnaire, along with effective donor education, to ensure its veracity. ID NAT testing is out of reach, as is pooled NAT testing, in many countries such as many in sub-Saharan Africa, where the incidence of HIV in the general population is expressed in double % digits. To significantly improve the safety of transfused blood, new technologies, such as PI, must be added to the already extensive battery of strategies [37]. Such systems have proven successful in preventing viral transmission when plasma and platelet components are treated [38]. They have been implemented in several European and Middle East countries, and FDA approval is being sought in the United States. So far, there is no available way to apply PI methods to red cells. The cost of such intervention has yet to be determined, but it will be undoubtedly quite high for the marginal increase in safety from HIV, HBV and HCV; but it may be worthwhile for emerging transfusion transmissible infections, especially for those agents for which we do not have effective tests or means to decrease their risks. Less common viruses Rarely, other identified viral infections have caused transfusion-transmitted infections. HAV is a food-borne illness that generally causes an acute clinical picture. As virtually all HAV infections are symptomatic, potential infectious donors would be eliminated by blood donor screening. There have been documented cases of transfusion-transmitted HAV [1], including remote cases involving transmission via contaminated factor VIII. HAV is not inactivated by solvent ⁄ detergent treatment, but HAV vaccines are available. Hepatitis E virus (HEV) infection, like HAV, is another enterovirus generally caused by fecally contaminated water. The presentation of HEV infection is similar to HAV, but subclinical infections are reported. Transfusion-transmitted HEV is rare, but has been reported. Antibody testing for HEV infection is generally used to test for infection, but PCR testing is available. A recent study from Japan showed the prevalence of anti-HEV in qualified blood donors to be 3Æ4% [39], slightly higher than that reported in the United States and Europe [1]. Like HAV, solvent-detergent treatment is not effective. Theoretically, PI would inactivate HEV as well as HAV. Conclusion Careful donor screening has been shown to eliminate the vast majority of HBV, HCV and HIV transfusion-transmitted viral infections over the past four decades. With viral specific antigen and antibody testing, viral-transmitted infections have been reduced another log. With NAT testing over the past decade, the risk of transmitting these infections through transfusion has been reduced further in the range of 1 in 300 000 for HBV to 1 in 2 million for HIV. For maximum reduction in risk, testing of units may not be able to reduce the rates of infection further. The best opportunity for near zero risk is treatment of the blood components directly, such as with PI. Although not approved worldwide, this technology has been shown to reduce the rate to near zero with the potential of eliminating extensive testing of all units [40]. PI has not been fully adopted and needs further investigation into the quantifying of pathogen reduction and toxicity. It has been suggested that, in addition to infectious disease testing which has reduced window period and established infections, PI could reduce transfusion-transmitted viral infections by reducing pre-NAT window period and occult infections [41]. Clinical studies proving this have not yet been performed. As PI does not rely on specific disease testing, it allows elimination of risk for yet unknown emerging infections. Furthermore, PI has been shown not to affect protein composition or clotting capacity [42]. A major limitation on this technology, however, is that is not available for use in red blood cells, although it has been suggested that treatment of whole blood before fractionation could assist in resolving this issue [43–45]. The challenge persists to develop a method capable of achieving the near zero risk of TTV from red blood cells. Careful donor selection remains the best way to prevent TTV before the unit is even collected and tested. 2010 The Author(s) Vox Sanguinis 2010 International Society of Blood Transfusion, Vox Sanguinis (2011) 100, 92–98 Transfusion transmission of hepatitis B, hepatitis C, and HIV 97 References 1 Dwyre DM, Holland PV: Hepatitis viruses; in Barbara JAJ, Regan FAM, Contreras MC (eds): Transfusion Microbiology. 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