International strategies to expand the donor pool have included closer scrutiny of donors at increased risk for blood borne virus transmission.
Transmission of blood borne viruses via solid organ transplantation can have a devastating impact on recipients.1,2 Risk of donor-derived infection transmission depends on baseline disease prevalence, which varies worldwide, donor risk assessment, via routine screening assessment of potential donors via clinical history, examination and blood tests, as well as factors including recipient immune status, organ transplanted and availability of prophylaxis.3 Underestimation of risk could lead to infection transmission to the organ recipient, but overestimation of risk may lead to missed opportunities for transplantation.
Although international guidelines typically demonstrate consensus regarding avoiding the highest risk cases, such as hepatitis B virus (HBV) and hepatitis C virus (HCV) nucleic acid test (NAT)-positive donors,4-6 variable recommendations exist in cases where risks are lower, as with HBV core antibody (HBcAb)-positive donors for nonliver solid organs. Use of HBcAb positive donors varies internationally (3.9% United States, 15% Italy, >50% Asian countries), related to baseline disease prevalence.7,8 Complicating decision making are advances in testing and treatment. NAT can safely expand the donor pool9,10; however, in low prevalence populations, false-positives may lead to organs being falsely rejected.11 HBV transmission risk can be mitigated by vaccination or posttransplant prophylaxis, but even after transmission, a single agent can effectively control viral replication. For HCV, direct-acting antiviral regimes are now available which can eradicate virus in under 24 weeks in more than 95% of individuals with treatment, even posttransplantation.12,13
Decisions under risk lead to biased decision making, with variable individual risk thresholds.14 In the complex transplantation context, this may tend to risk aversion, although this is not well studied.15 There is variable treatment of increased risk donors within countries as seen in recent work from Canada.16
In the current context, the best transplant decisions are not always clear for clinicians, whereas understanding of hepatitis status is increasingly important. This study aimed to survey clinicians’ understanding of abnormal HBV and HCV serology in a kidney transplant setting. Specifically, we aimed to identify specific clinical scenarios where there were gaps in understanding of hepatitis risk of potential donors or recipients or variability in transplant suitability responses either from current regional guidelines or among clinicians.
MATERIALS AND METHODS
We performed a cross-sectional survey of practicing clinicians involved in kidney donation and transplantation in Australia and New Zealand. This included not only primarily nephrologists but also transplant hepatologists, intensive care doctors, and transplant surgeons. This approach mirrors the clinical practice in Australia and New Zealand, where all these groups impact suitability decisions at the time of donor referral and transplant acceptance.
The survey was hosted via the University of Sydney server, as an open Web-based survey, accessible via public link. Functionality included ability to review previous answers and to save responses and return to the survey. Eligibility was assessed by self-reporting. Responses were anonymous and voluntary with no incentives.
We invited participation via email lists of the Transplantation Society of Australia and New Zealand (TSANZ), Australia and New Zealand Society of Nephrologists, Australia and New Zealand Intensive Care Society, regional and national transplant advisory committees as well as emails to more informal groups including transplant surgeons and transplant hepatologists. Targeted appeals from individual clinicians and repeat emails from learned societies helped to increase response numbers. The survey was open for 4 months from December 2014 to April 2015.
Survey Format and Content
The survey was a scenario-based, electronic survey, comprising 8 clinical scenarios with HBV or HCV serology results for a potential kidney deceased donor and recipient pair. The scenarios were devised to reflect clinically relevant and realistic higher-risk situations that were likely to pose a challenge to respondents. As an internal validity check, 1 scenario was designed with more common, benign serology, for which all respondents were expected to demonstrate good understanding. Respondents were presented with scenarios in random order (to reduce the impact of learning during the survey). For each scenario, respondents answered 3 mandatory multiple-choice questions to identify (i) donor hepatitis status, (ii) recipient hepatitis status, and (iii) transplant suitability of the donor-recipient pair. Wording was designed to reflect options presented in the regional guidelines.17 An option of “unsure” was provided for each multiple-choice question. The survey was piloted internally before distribution to test usability. The survey was amended in response to pilot participant feedback to produce the final questionnaire (see Appendix 1, SDC, http://links.lww.com/TP/B469).
Ethics was obtained from Sydney University Human Research Ethics Committee; project number 2014/1016, on November 28, 2014. All survey respondents had access to a Participant Information Statement, and a summary of this was provided both in the approved contact email and on the first page of the survey. Consent was implied by participation beyond this point.
Outcomes and Analysis
Outcomes were guideline-concordant17 interpretation of (i) donor infection status, (ii) recipient infection status and (iii) each pair’s suitability for transplantation. In those scenarios with poor (<50%) guideline concordance for transplant suitability, univariable and multivariable logistic regression models were fitted to (i) the guideline-concordant answer, and (ii) the most common alternative answer, to identify any factors associated with these outcomes. Potential factors considered were: role (nephrologists, intensive care and other, transplant surgeons, hepatologists), sex, age (<40, 40-50, 50-60, 60+ years), transplant practice patient burden (<20, 20+ per month), involvement in acute phase of transplant care, awareness of guidelines (strongly agree or agree, strongly disagree, disagree, or neutral), and location (Queensland, New South Wales, Victoria, New Zealand, other). A random effect for participant was included in all models, as participants answered multiple scenarios. Scenario was included as a categorical variable in the model to account for scenario difficulty. All factors were initially entered into the multivariable models and removed using stepwise backwards elimination, with factors remaining in the final model if statistically significant (P < 0.05); with the exception of role, which remained in all multivariable models, regardless of its p value.
Only complete questionnaires were used for analysis. Demographic characteristics of incomplete responses were compared with eligible responses using univariable logistic regression. Demographic characteristics of the respondent population were compared with workforce estimates.18
We included 110 respondents accrued over 4 months, with 61 respondents excluded as shown in Figure 1. Reasons for exclusion were incomplete survey responses, ineligible respondents, and 1 case of technical error. When compared with workforce characteristics, demographics were broadly consistent.18 Among eligible respondents of complete versus incomplete survey, responses demonstrated no significant difference in sex (P = 0.37) or clinical roles (P = 0.06), but did find significant differences in age (P = 0.04) and in location (P = 0.03), with respondents aged over 60 years and from New Zealand both underrepresented in the final analysis set.
Characteristics of eligible respondents are shown in Table 1. Most respondents (50%) reported caring for an average 1 to 20 transplant patients per month and were aware of clinical practice guidelines (51%, agree; 9%, strongly agree). The majority (70%) worked in full time clinical practice, and 24% respondents were engaged in research. Sixty-one percent provided acute transplant care at a transplanting center.
Figures 2 and 3 present the responses to each question for HBV and HCV, respectively. High levels of concordance within the internal validity check scenario suggested that the survey of novel design is a valid instrument.
Interpretation of Donor and Recipient Risk Status
Both donor and recipient hepatitis status were generally well identified across the scenarios (Table 2), with greater than 90% appropriate risk attribution in the majority of scenarios. In 1 HBV scenario, 62% respondents identified a HBcAb-positive and HBV surface antibody (HBsAb)-positive donor as a low risk for hepatitis transmission, in concordance with current guidelines, but 30% suggested this donor posed no hepatitis transmission risk. In 2 scenarios with HBV surface antigen (HBsAg)-positive donors, an average of 11% of the respondents incorrectly suggested this as low risk rather than high risk. For an isolated HBcAb-positive recipient, 18% respondents had incorrect answers evenly split among 3 alternative responses to the correct “exposed, no active virus.”
In 2 scenarios with HCV antibody (HCV-Ab)-positive HCV NAT-negative donor, this was identified as a hepatitis transmission risk by an average of 35% respondents, in concordance with guidelines. However, the majority of respondents (average, 60%), including all responding hepatologists, suggested this donor posed no HCV transmission risk.
Concordance of Transplant Suitability Decisions
Transplant suitability decisions showed widespread variability in responses among clinicians and discordance from guidelines. Excluding the validity check scenario, the highest rate of guideline concordance was 81%, which fell rapidly in other scenarios. In 4 scenarios (2 HBV, 2 HCV), guideline concordance was less than 50%. In 2 scenarios, the most popular alternative was selected more than guideline concordant responses. With donor and recipient both HCV-Ab-positive HCV NAT-negative, only 7% selected the guideline concordant “unsuitable” response, where 63% selected an alternative “suitable with consent” response. For an HBV exposed, low-risk donor (HBcAB-positive, HbsAb-positive) and naïve recipient, 48% selected “suitable with prophylaxis” (guideline divergent), whereas only 20% selected the guideline concordant “suitable with informed consent.” Two scenarios had a more even split between guideline concordant and most popular alternative response: HCV-Ab-positive HCV NAT-negative donor and HCV-naive recipient (47% unsuitable, guideline concordant; 35% suitable with consent, guideline divergent), and active donor infection (HBcAb positive, HBsAg positive, HBsAb negative) and immunized recipient (isolated HBsAb positive) where 44% selected the guideline concordant response “unsuitable” and 35% selected the most common alternative response “suitable with consent and prophylaxis.”
Suitability responses at times showed a wide spread of attitudes among respondents. For example, in a HBV scenario with an exposed donor (HBcAb positive, HBsAg negative, HBsAb positive) and a naive recipient, 15% deemed the transplant as suitable without any special measures, and 13% deemed the transplant unsuitable.
Across the 7 higher-risk scenarios, an average of 6% of the respondents self-identified as “unsure.” Variability in suitability responses persisted even where hepatitis status of both donor and recipient were nearly universally recognized.
The results of the univariable and multivariable models for transplant suitability outcomes in the 4 HBV and HCV scenarios where guideline concordance was less than 50% are presented in Figure 4 (full results Appendix 2, SDC,http://links.lww.com/TP/B469). Location was a strong factor influencing responses, with New Zealanders less likely to respond in concordance with guidelines (odds ratio [OR], 0.17; 95% confidence interval [CI], 0.06-0.46; P < 0.01), and more likely select the most common alternative response (OR, 4.31; 95% CI, 1.99-9.35, P < 0.01). Role was a significant factor for differences in guideline concordance (P = 0.01) with hepatologists (OR, 0.23; 95% CI, 0.06-0.92) and intensive care specialists (OR, 0.35; 95% CI, 0.18-0.82) less guideline concordant in these scenarios. Care of transplant patients in the acute setting at a transplanting center was associated with more guideline concordant responses (OR, 1.69; 95% CI, 1.01-2.80; P = 0.04). Awareness of guidelines, transplant patient burden, sex, and age were not predictive of guideline concordant or most popular alternative responses.
This survey of transplant clinicians showed good understanding of hepatitis serology of donors and recipients. Despite this, translation to consistent transplant suitability decisions was highly variable.
What is the reason for variable transplant decisions when donor serology is correctly interpreted? Awareness of guidelines does not appear to be the primary issue, as only 22% self-identified as unaware of where to find current guidelines. Further, awareness of guidelines did not have an impact on transplant suitability responses (ie, those aware of guideline recommendations were not more or less likely to answer in concordance with them). This suggests either a lack of understanding of current guidelines or more likely that clinical evidence has outpaced guidelines. Australian and New Zealand guidelines, last published in 2011, were updated during this study.19 Notable changes include support for consideration of higher-risk serology scenarios, including HCV-positive donors, and consideration of prophylaxis for HBcAb-positive donors, although other recommendations remain conservative.
Are regional or personal preferences driving practice? To identify any shift in contemporary practice, we examined factors influencing suitability responses in scenarios where less than 50% of the respondents answered according to the guidelines. Hepatologists were perhaps more progressive in attitude, being less guideline concordant, and tending to select the most common alternative response (P = 0.07). In the TSANZ network, transplant hepatologists can provide guidance on hepatitis infections to other transplant clinicians, hence these responses may suggest that guidelines are too risk averse. Respondents involved in acute transplant care at a transplanting center, who are likely to be making more frequent suitability decisions than other respondents, selected more guideline concordant responses, however. New Zealand clinicians were less likely to select guideline concordant responses and more likely to respond with the most common alternative response, which supports the hypothesis of emerging differences in practice. If outdated guidelines were the sole problem, we would expect less interclinician variability than what was demonstrated. This study was unable to discern variations in practice between individual centers or groups, because data were not captured at this level.
Does the wider literature and international guidelines provide support for alternative suitability responses and explain variability? With HBV, once natively infected, the potential for reactivation always remains despite being HBV NAT-negative because there is an ongoing reservoir for the virus in the liver. HBV can incorporate in the genome and is maintained in covalently closed circular deoxyribonucleic acid form, which cannot be eliminated and has potential for future reactivation. This is in distinct contrast to HCV. Recent literature on HBcAb-positive kidney donors demonstrated no clinical impact on recipients and low rates of HBsAg seroconversion.20 Despite this, international clinical practice guidelines vary, suggesting such donors are unsuitable,6 require routine prophylaxis,21 prophylaxis depending on recipient HBsAb titre4 or donor HBV NAT positivity,22 or treatment of recipient only after seroconversion.20 The most recent Australasian guidelines emphasize prophylaxis for recipients.19 This is consistent with the most common guideline-divergent response (48%), suggesting that those respondents may have been more pragmatic than previous guidelines.
Where donors are HBsAg positive, the risk of transmission is low in certain circumstances (such as with nonliver solid organs, if donor HBV NAT is negative, to an immunized recipient and with prophylaxis), and a recent study suggests that there was no difference in outcomes for recipients receiving HBsAg-positive donor organs.23 Indeed, some literature suggest using these donors for recipients in kidney transplantation, with appropriate treatment posttransplant depending on recipient vaccination status.24 However, concerns remain given at least 1 recently publicized case of fulminant hepatic failure in a kidney recipient of such an organ.2 International guidelines hence typically advise against use of these donors except in life-threatening cases. It may be that informed respondents were being less conservative than guidelines, but the wide variation in responses remains notable.
The risk of transmission from HCV-Ab-positive HCV NAT-negative donors remains to be fully defined6; this was 1 area respondents had difficulty in interpreting serology. Fluctuating viremia is possible and may still pose a transmission risk, despite sparse evidence of transmission in nonliver solid organ transplantation. Thus, interpreting this as a no risk scenario (58% responses) was incorrect. Current guidelines recommend against the use of these donors except for HCV NAT-positive recipients. However, once an individual is documented to be HCV NAT-negative on 2 separate occasions 12 weeks apart, or on a single occasion more than 12 weeks after any at risk exposure, they are deemed clear of the virus. This highlights that HCV has no reservoir of infection and needs ongoing viral replication for maintenance of infection. A range of new direct-acting antivirals are available that can be used in renal impairment and can achieve HCV eradication with 8 to 24 weeks of treatment in 95% to 100% of individuals.12 There has been increasing acceptance in transplant centers to eradicate HCV both pretransplant and posttransplant,13 and very recent changes to the local TSANZ guidelines regarding consideration of HCV positive donors for negative recipients, similar to recent international position statements.19,25 Respondents may have been preempting these updates.
A strength of our work is that we gathered a representative sample of the regional nephrology workforce, by age, sex, and location, compared with national workforce surveys.18 Our survey distribution method was broadly inclusive, because there is no clear denominator of eligible clinicians to approach. The limitation of extending an invite to participate very broadly is that we cannot estimate a response rate. Certainly, low absolute numbers of respondents in some comparator subgroups, especially transplant hepatologists, limit inferences that can be made and generalizability in these groups. As with any survey, we cannot rule out selection bias from respondent self-selection, but we would expect volunteer responders to be more engaged with this area and perhaps demonstrate more knowledge than the wider pool. Our comparison of incomplete versus complete responses demonstrated some differences in characteristics, which could be due to difficulties encountered by some subgroups accessing the survey due to hospital firewalls and outdated internet browser software.
Although the results of this study are likely to be generalizable across the wider Australia and New Zealand transplant workforce, whether they are generalizable beyond this is less certain. Previous studies investigating variability in transplant suitability with abnormal hepatitis serology were confined to limited HBV scenarios in liver transplants26,27; no similar studies have applied such a broad range of cases or considered renal transplantation. Limited studies considering donors with risk factors for blood borne viruses also showed variability in transplant clinician attitudes and practice.16,28,29 Whether clinicians’ real-life decision making mirrors their responses to theoretical scenarios is uncertain, noting this survey focused on virological risk alone and did not capture the myriad of other considerations that may impact on decision making by clinicians including an individual's waiting time, illness severity, and their values and preferences.
To address residual uncertainties, an audit of increased-risk hepatitis donor referrals to understand handling of these cases in real-world conditions would be informative. Systematic review of clinical practice guidelines and the evolving evidence base would also provide a strong foundation to build consensus response. Exploring whether similar variability persists in other countries and as guidelines evolve would also be of interest.
Noting the speed at which this field is evolving, and that guidelines by nature cannot always keep up with emerging evidence, real-time decision support or consensus opinion on such controversial areas that is updated by trusted clinicians would be of value. Given the complexity of the area, developing targeted education programs for clinicians making these high-impact decisions in fast-paced environments may also help to build more consistency in approach.
The application of knowledge of hepatitis risk in scenarios with donors and/or recipients with abnormal hepatitis serology is an area of demonstrable uncertainty among transplant clinicians. This is despite good isolated understanding of donor and recipient hepatitis risk status. The results of this study suggest a complex pattern of factors underpinning variability in clinical approach to abnormal hepatitis serology, where guidelines do not always support most current evidence-based practice.
Given the clinical implications of decision-making in this area at both an individual patient level and a broader public health perspective, this study suggests that there is a role for more pragmatic guidance to support consistent treatment of higher-risk hepatitis scenarios and hence improve clinical practice.
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2. Magiorkinis E, Paraskevis D, Pavlopoulou ID, et al. Renal transplantation from hepatitis B surface antigen (HBsAg)-positive donors to HBsAg-negative recipients: a case of post-transplant fulminant hepatitis associated with an extensively mutated hepatitis B virus strain and review of the current literature. Transpl Infect Dis
3. Ison MG, Grossi P. AST Infectious Diseases Community of Practice. Donor-derived infections in solid organ transplantation. Am J Transplant
4. Scandiatransplant Working Group. Guidelines for prevention of transmission of infectious diseases from organ donors to recipients. http://www.scandiatransplant.org/members/prevention-of-transmission-of-infections/ScandtxInfGuidelines20April20162.pdf
. Published 2015.
5. The Advisory Committee on the Safety of Blood Tissues and Organs (SaBTO). Guidance on the microbiological safety of human organs, tissues and cells used in transplantation. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/215959/dh_130515.pdf
. Published February 21, 2011.
6. Fischer SA, Lu K. AST Infectious Diseases Community of Practice. Screening of donor and recipient in solid organ transplantation. Am J Transplant
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7. Health Resources and Services Administration. OPTN & SRTR Annual Data Report 2011. https://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/2011_SRTR_ADR.pdf
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8. Salvadori M, Rosso G, Carta P, et al. Donors positive for hepatitis B core antibodies in nonliver transplantations. Transplant Proc
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13. Kwo PY, Mantry PS, Coakley E, et al. An interferon-free antiviral regimen for HCV after liver transplantation. N Engl J Med
14. Kahneman D, Tversky A. Prospect theory: an analysis of decision under risk. Econometrica
15. Schnier KE, Cox JC, McIntyre C, et al. Transplantation at the nexus of behavioral economics and health care delivery. Am J Transplant
16. Kumar D, Humar A, Kim SJ, et al. A survey of increased infectious risk donor utilization in Canadian Transplant Programs. Transplantation
17. The Transplantation Society of Australia and New Zealand (TSANZ). Organ transplantation from deceased donors: consensus statement on eligibility criteria and allocation protocols, Version 1.3. https://www.tsanz.com.au/downloads/ConcensusStatementV1.38Jan2014_000.pdf
. Published January 8, 2014.
19. The Transplantation Society of Australia and New Zealand. Clinical guidelines for organ transplantation from deceased donors version 1.1. http://www.tsanz.com.au/organallocationguidelines/documents/ClinicalGuidelinesV1.1May2017.pdf
. Published May 2017.
20. Mahboobi N, Tabatabaei SV, Blum HE, et al. Renal grafts from anti-hepatitis B core-positive donors: a quantitative review of the literature. Transpl Infect Dis
21. Huprikar S, Danziger-Isakov L, Ahn J, et al. Solid organ transplantation from hepatitis B virus–positive donors: consensus guidelines for recipient management. Am J Transplant
22. Levitsky J, Doucette K. AST Infectious Diseases Community of Practice. Viral hepatitis in solid organ transplantation. Am J Transplant
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23. Chancharoenthana W, Townamchai N, Pongpirul K, et al. The outcomes of kidney transplantation in hepatitis B surface antigen (HBsAg)–negative recipients receiving graft from HBsAg-positive donors: a retrospective, propensity score-matched study. Am J Transplant
24. Pilmore HL, Gane EJ. Hepatitis B-positive donors in renal transplantation: increasing the deceased donor pool. Transplantation
25. American Society of Transplantation. Utilization of hepatitis C positive donor organs in transplantation of hepatitis C negative recipients. https://www.myast.org/public-policy/key-position-statements/utilization-hepatitis-c-positive-donor-organs-transplantation
. Published August 12, 2016. Accessed May 26, 2017.
26. Perrillo R. Hepatitis B virus prevention strategies for antibody to hepatitis B core antigen-positive liver donation: a survey of North American, European, and Asian-Pacific transplant programs. Liver Transpl
27. Burton JR Jr, Shaw-Stiffel TA. Use of hepatitis B core antibody-positive donors in recipients without evidence of hepatitis B infection: a survey of current practice in the United States. Liver Transpl
28. Kucirka LM, Namuyinga R, Hanrahan C, et al. Provider utilization of high-risk donor organs and nucleic acid testing: results of two national surveys. Am J Transplant
29. Akolekar D, Oniscu GC, Forsythe JL. Variations in the assessment practice for renal transplantation across the United Kingdom. Transplantation