1



## PHS G UIDELINE FOR REDUCING TRANSMISSION OF HUMAN

IMMUNODEFICIENCY VIR US 

## ( HIV 

## ), HEPATITIS B VIRUS 

## ( HBV 

## )
,

AND H EPATITIS C VIRUS 

## ( HCV 

## ) THROUGH SOLID ORGAN

T RANSPLANTATION

Debbie L Seem, RN, MPH 1 , Ingi Lee, MD, MSCE 2 , Craig A Umscheid, MD, MSCE 2

, and

Matthew J Kuehnert, MD 1

1 D ivision of Healthcare Quality Promotion
Centers for Disease Control and Prevention Atlanta, GA

2 Center for Evidence

- based Practice University of Pennsylvania Health System Philadelphia, PA

Disclaimer: This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the Centers for Disease Control and Prevention. It does not represent and should not be construed to represent any agency determination or policy

.2



### Acknowledgement

We would like to recognize Jonathan R. Treadwell, Ph.D., Senior Research Analyst, and Meredith Noble, M.S., Senior Research Analyst, from the Evidence

- based Practice Center, ECRI Institute, Plymouth Meeting, PA, who authored Solid Organ Transplantation and the Probability of Transmitting HIV, HBV, or HCV: A Systematic Review to Support an Evidence

- b ased
Guideline , referred to as the Evidence Report in this guideline

.

The Expert Panel and Review Committee contributed throughout the guideline development process and provided in

- depth review of the key evidence search questions, bibliography resulting from the literature review, and draft evidence report. Further input was sought from subject matter experts to address specific issues in development of the guideline; in particular, we express our thanks to Scott Halpern, MD, PhD, MBE, Michael G Ison, MD, MS, and Jutta Preiksaitis, MD, for writing the original drafts of the Expert Opinion summaries.

The opinions of indiv idual members of the Expert Panel or Review Committee might not be
reflected in all the recommendations herein, as the guideline represents the position of the Public Health Service agencies , and is not a consensus document

.



### Expert Panel

Branson, Bernard, MD Associate Director for Laboratory Diagnostics, Office of the Director, Division
of HIV/AIDS Prevention , NCHHSTP ; Centers for Disease Control and Prevention

Grohskopf, Lisa A , MD , MPH
Medical Officer, Epidemiology Branch, Division of HIV/AIDS Prevention, NCHHSTP; Centers for Disease Control and
Prevention

Holmberg, Scott, MD, MPH Chief, Epidemiology and Surveillance
Branch

, Division of Viral Hepatitis, NCHHSTP; Centers for Disease Control and
Prevention

Thompson, Nicola D, PhD, MS Epidemiologist, Epidemiology and
Surveillance Branch

, Division of Viral Hepatitis, NCHHSTP; Centers for Disease
Control and Prevention 

### Review Co mmittee

Bridges, Nancy D, MD Chief, Transplantation Immunobiology Branch; National Institute of Allergy and Infectious Diseases; National Institutes of
Health

DeMaria, Alfred, Jr, MD Medical Director, Bureau of Infectious
Disease Prevention

, Response and Services ; State Epidemiologist; Massachusetts Department of Public Health ; Council of States and Territorial Epidemiologists Representative

Durbin, Richard C, MBA Director, Division of Transplantation, Healthcare Systems Bureau; Health
Resources and Services Administration3



### Review Committee cont.

Fishman, Jay A, MD Associate Director, MGH Transplantation Center; Director, Transplant Infectious Disease and Compromised Host Program; Massachusetts General Hospital; Professor of Medicine, Harvard Medical School

Holmberg, Jerry A, PhD Senior Advisor for Blood Policy

, Office of
the Secretary, Office of the Assistant Secretary for Health; U .S. Department of
Health and Human Services

St. Martin, Laura, MD, MPH
Medical Officer

, Division of Human
Tissu es; Food and Drug Administration

Tritz, Karen L, MSW Technical Director, Division of Continuing
Care Providers Survey and Certification Group ; Centers for Medicare and Medicaid
Services

Ziermann, Rainer, PhD Senior Director, Clinical Research Roche Molecular Systems4 

### Disclosure of Financial Interests and Relationships

We requested guideline authors and Expert Panel members to report conflicts of interest. The authors DLS, IL, CAU and MJK report no actual or potential conflicts of interest. IL and CAU received funding from CDC to support the guideline development process. No Expert Panel members reported conflicts of interest

.5 

### Table of Contents

Abbreviations

................................ ................................ ................................ ................................ ... 6

I. Executive Summary

................................ ................................ ................................ ............. 8

II. Summar y of Recommendations

................................ ................................ ......................... 11

II I

. Recommendations for Further Research

................................ ................................ ............ 18

I V. Scope and Purpose

................................ ................................ ................................ ............. 20

V. Background

................................ ................................ ................................ ........................ 22

VI. Methods

................................ ................................ ................................ ............................. 26

VII . Evidence Review

................................ ................................ ................................ ............... 38

Expert Opinion Summaries.................................................................

.... ... .85

VIII . Appendices

................................ ................................ ................................ ......................... 91

References

................................ ................................ ................................ ................................ .... 1466 

### Abbreviations

ALT Alanine aminotransferase

Anti

- HBs Antibody to hepatitis B surface antigen

Anti

- HBc Antibody to hepatitis B core antigen

Anti

- HCV Antibody to hepatitis C virus

Anti

- HIV Antibodies to h uman immunodeficiency virus , types I and II

CDC Centers for Disease Control and Prevention

CSW Commercial sex worker

DNA Deoxyribonucleic acid

EDTA E thylenediaminetetraacetic acid

EIA Enzyme immunoassay

ELISA Enzyme

- linked immunoassay

FDA Food and Drug Administration

GRADE Grading of Recommendations Assessment, Development, and Evaluation

HAART H ighly active anti

- retroviral therapy

HBIG H epatitis B immune globulin

HBsAg Hepatitis B surface antigen

HBV Hepatitis B virus

HCV Hepatitis C virus

HHS U.S. Department of Health and Human Services

HIV Human immunodeficiency virus

HMO H ealth maintenance organization

HRSA Health Resources and Services Administration

HSV Herpes simplex virus

IDU Injection drug use

IVDU Intravenous drug use

IgG anti

- HBc Immunoglobulin G antibodies to hepatitis B core antigen

IgM anti

- HBc Immunoglobulin M antibod i es to hepatitis B core antigen

IRD Increased risk donor

IVDU I ntravenous drug use

MSM Men who have sex with men

NAT Nucleic acid test7 NHANES National Health and Nutriti on Examination Survey

OPO Organ procurement organization

OPTN Organ Procurement and Transplantation Network

PCR Polymerase chain reaction

PHS Public Health Service

PPV Positive predictive value

RCT Randomized controlled trial

RIBA R ecombinant immunoblot assay

RNA Ribonucleic acid

RT

- PCR Reverse transcriptase polymerase chain reaction

SOT Solid organ transplantation

SRTR Scientific Registry of Transplant Recipients

STD Sexually transmitted disease

UNOS United Network for Organ Sharing

QALYs Quality of life years8 

## I. Executive Summary

This guideline supplants the 1994 Public Health Service ( PHS ) Guidelines for Preventing Transmission of HIV through Transplantation of Human Tissue and Organs

. 1 The most significant changes involve :

● expanding the guideline to include hepatitis B virus (HBV) and hepatitis C virus (HCV), in addition to human immunodeficiency virus (HIV);

● u tilizing factors known to be associated with increased likelihood of HIV, HBV or HCV to identify potential donors at increased risk for transmitting infection ;

● distinguishing between expected and unexpected transmission of HBV and HCV in goals for prevention;

and

● limiting the focus to solid organ transplants and vessel con duits recovered for organ transplant purposes

. As with the 1994 guideline, the recommendations address adult and pediatric donors who are living or deceased, as well as transplant candidates and recipients.

T ransmission of HIV, HBV and HCV through organ transplantation is a critical patient safety and public health issue. Such events can result in serious illness and death in organ recipients who are immunosuppressed, particularly when transmission is unexpect ed

. In this situation, the recipient can unintentionally infect others

, creating the need for infection control response in both the healthcare and community settings . Unexpected
transmission of HIV , HBV and HCV from infected donors has been reported in he art, liver, kidney and pancreas recipients. 2

- 11 However, intentiona l transplantation of organs from HBV

- and HCV

- infected donors is accepted medical practice in narrowly specified situations . These organs are typically offered to recipients known also to be infected with the same pathogen, or in rare circumstances, to un infected recipients in cases of urgent medical need where benefit is deemed to outweigh risks. In these situations, prophylaxis or treatment with immunizations, anti

- virals and/or immunoglobulin is offered

, if appropriate

, to prevent transmission or
reduce the disease severity. Although there may be a potential benefit of transplanting organs from HIV

infected donors into HIV

- infected recipients, Organ Procurement and Transplantation Network (OPTN) policy, as required by the HHS Final Rule [ 42 CFR Part 121 ], prohibits the knowing acquisition and transplantation of organs infected with HIV.

The purpose of this document is to provide guidance to organ procurement organizations (OPOs); transplant

centers, including physicians, nurses, administrators, and clinical coordinators; laboratory personnel responsible for testing and storing donor and recipient specimens; and persons responsible for developing, implementing, and evaluating infection prevention and control programs for OPOs and transplant centers

. In constructing this guideline, the PHS sought assistance from public and private health professionals and representatives of transplantation, organ recovery, public health and other organizations.

This g uideline is based on a targeted systematic review of the best available evidence, with explicit links between the evidence and recommendations. To accomplish this, we used an adapted GRADE approach for evaluating quality of evidence and determining strengt h of recommendations. The methodology, structure, and components of this guideline are approved by the Centers for Disease Control and Prevention (CDC ) . A more detailed description of our approach is available in the Methods section

. 12

To evaluate the evidence on reducing transmission of HIV, HBV and HCV , we examined data addressing 10 key questions within five major topic areas (Table 1) . A sixth topic area includes questions addres sed by Expert Opinion (EO)

. We drew upon expert s to draft summaries related to th ese questions anticipating that a systematic review of the literature would produce insufficient evidence

- based data

. The summaries were written
and edited by the guideline authors

.9 Table 1

. Questions for Systematic Review

Major topic area of the guideline Question for Systematic Review

I. Probability of transmission of HIV, HBV, or HCV through solid organ transplantation (SOT) 1. What are the prevalence and incidence rates of HIV, HBV, and HCV among potential solid organ donors?

2. What are the rates of transmission to recipients from donors infected with HIV, HBV, or HCV? Do the rates vary by the organ transplanted or when the donor was infected?

II. Method ology to better estimate donor infection with HIV, HBV, or
HCV 3. What behavioral risk factors are associated with an increased probability of infection with HIV, HBV, or HCV? What is the prevalence of these characteristics among potential solid organ donors?

4. What nonbehavioral factors are associated with an increased probability of infection with HIV, HBV, or HCV? What is the prevalence of these factors among potential solid organ
donors?

5. What are the test characteristics of the screening methods available to detect HIV, HBV, and HCV in potential solid organ donors? Do test characteristics differ in particular populations and with donor clinical status (i.e., donation
after brain death v ersus donation after cardiac death OR adult vs. pediatric donors)?

III. Donor interventions to decrease transmission of HIV, HBV, or HCV
from infected donors 6. Which donor interventions reduce the probability of pathogen transmission from an organ donor infected with HIV, HBV, or HCV to a previously uninfected recipient?

IV. Potential risks and benefits of transplanting, or not transplanting, solid organs from donors positive
for HIV, HBV, or HCV 7. How do the clinical outcomes of recipients of organs from donors infected with HIV, HBV, or HCV compare to those who remain on the transplant list?

V. Potenti al risks and benefits of transplanting, or not transplanting, organs from donors with risk
factors for HIV, HBV, or HCV 8. How do the clinical outcomes of transplant recipients who receive organs from donors with behavioral or nonbehavioral risk factors compare to those who remain on the transplant list?

9. What is the impact of excluding potential solid organ donors with behavioral or nonbehavioral risk factors on the organ donor pool?

10. What is the impact of false positive tests on the organ donor pool?10 Major topic area of the guideline Question for Systematic Review

VI. Approaches to informing recipients
about the risk s of HIV, HBV, and
HCV transmission and evaluat ion for possible exposure post

transplantation

Note: The related three questions were not part of the systematic literature
review. EO1. How and when should informed consent be obtained from potential recipients to help them consider the risks (i.e., probability of acquiring the disease and consequenc es of disease acquisition) of donor

- derived HIV, HBV, and HCV?

EO2. When should testing of a transplant recipient be done to
detect HIV, HBV, and HCV transmission from the donor?

EO3. How should donor and recipient specimens be collected and stored for pot ential investigation of donor

- derived HIV, HBV, and HCV infection?

Evidence addressing the key questions was used to formulate recommendations and is available in the Evidence
Review in the body of the guideline and the GRADE Tables in the appendices. Evidence

- based
recommendations were cross

- checked with those from previously published guidelines identified in an initial systematic search.

The guideline authors used the narrative evidence summaries to develop guideline recommendation s. If weighing the critical outcomes for a given intervention or question resulted in a net benefit or a net harm, then a Category I Recommendation was formulated to recommend strongly for or against the given intervention respectively. If weighing the cri tical outcomes for a given intervention or question resulted in a tradeoff between benefits and harms, then a Category II Recommendation was formulated to recommend that providers or institutions consider the intervention when deemed appropriate.

L evels A and B represent the quality of the evidence underlying the recommendation, with A representing high to moderate quality evidence and B representing low to very low

- quality evidence. Level IC represents required practices, regardless of the quality of evid ence.

Expert Opinion. Recommendations from the Expert Opinion are linked to key questions. These recommendations were agreed upon by expert consensus and are designated either IB if they represent a strong recommendation based on accepted practices or IIB if they are a weak recommendation

.

Recommendations from previous guidelines or reports for topics not directly addressed by our systematic
review of the evidence were included in our Summary of Recommendations if they were deemed critical to the
target users of this guideline. Unlike recommendations informed by our systematic review, these recommendations will not be linked to a key question and were listed as Category I recommendations as the
critical outcome for each intervention was determined to resu lt in a net benefit

.

The Summary of Recommendations is organized as follows : 1) Donor risk assessment; 2) Donor screening; 3)

HBV

- infected donors and transplantation; 4) HCV

- infected donors and transplantation; 5) Recipient i nformed consent; 6) Recipient testing ; 7) Donor and recipient specimen collection and storage; and 8) Tracking and reporting of HIV, HBV, and HCV.

Areas in need of further research identified during the evidence review are outlined in the Recommendations for
Further Research . This sec tion includes guidance for specific methodological approaches that should be used in future studies, such as the use of clinically relevant outcome measures.

Readers who wish to examine the primary evidence underlying the recommendations are referred to the
Evidence Review in the body of the guideline

, GRADE Tables (from the Evidence Report) in the Appendices

,11 and the Evidence Report accessible at http:// www.regulations.gov

. The Evidence Review includes narrative summaries of the data presented in the Evi dence Report

. In the Evidence Report , t he Evidence Tables include all study

- level data used in the guideline, and the GRADE Tables assess the overall quality of evidence for each question. Finally, the Evidence Report present s a clearly delineated search strategy that will be used for periodic updates to ensure that the guideline remains a timely resource as new information becomes available.



## I I. Summary of Recommendations

Table 2 . Categorization Scheme for Recommendations

Category IA Strong recommendation supported by high to moderate quality evidence

suggesting net clinical benefits or harms.

Category IB Strong recommendation supported by low to very low quality evidence

suggesting net clinical benefits or harms.

Category IC Strong recommendation required by state or federal regulation , regardless

of the quality of evidence

.

Category IIA Weak recommendation supported by high to moderate quality evidence

suggesting a trade

- off between clinical benefits and harms.

Category IIB Weak recommendation supported by low to very low quality evidence

suggesting a trade

- off between clinical benefits and harms.

No recommendation Unresolved issue for which there is any quality evidence with uncertain

trade

- offs between clinical benefits and har ms.

Category I: R ecommendations not linked to a key question and no systematic review of the literature performed , but the critical outcome was determined to result in a net benefit

.

If a recommendation was based on evidence for one of the 10 key question s , the key question was referenced (e.g., Question 3) ; t he Evidence Review for the key questions starts on page 3 8

. If a recommendation was based

on evidence for one of the three Expert Opinion questions , the Expert Opinion question was referenced (e.g., Expert Opinion

– Question 1) ; t he Expert Opinion summaries start on page 8 5

. Additional information on categorizing the recommendati on can be found under Formulating Recommendations starting on page 3 5

.

It is important to clarify that when recover ed or transplanted organs are referred to in the following recommendations, associated vessels are also implied since these vessel conduits may be transplanted with the recovered donor organ or with a recipient of an organ from a different donor.

Donor Ri sk Assessment

1. All prospective living donors and individuals interviewed about deceased potential organ donors (i.e., next of kin, life partners, cohabitants, friends, healthcare provider) should be informed of the general natur e of the donor evaluation process, including the review of medical and behavioral history, physical examination,
and blood tests to identify the presence of infectious agents or medical conditions that could be transmitted by organ transplantation. ( Catego ry I )12 2. To ascertain whether potential organ donors are average risk or at increased risk for having HIV, HBV, or HCV, prospective living donors and next

- of

- kin, as well as individuals familiar with deceased donors (i.e., life partners, cohabitants, friends, healthcare provider), should be interviewed in a confidential and sensitive manner about behaviors that may have increased the potential donor‟s probability of HIV, HBV or HCV infection. (Refer to Table 3 for risk factors) ( Category IB ) (Questions 3/4A)

3. For prospective living donors with a history of behaviors associated with an increased risk of acquiring HIV, HBV or HCV identified during evaluation, individualized counseling and a detailed discussion of specific strategies to prevent exposure to these viruses should occur ; however, in most circumstances a discussion of strategies to avoid these behaviors should be provided. (Refer to Table 3 for risk factors) ( Category 1 )

4. For potential pediatric donors for whom maternal transmission of HIV, HBV or HCV infection is a consideration, the mother and, if possible, the father should be interviewed about behaviors that may have placed them at risk for acquiring an infection that could have been transmitted to their child. ( Category I )

5. Children with any risk factors associated with increased probability of HIV, HBV or HCV should be
identified as having an increased probability of HIV, HBV or HCV infection . ( Category IB ) (Questions 3/4B)

6. Children ≤ 2 years of age born to mothers with HIV, HBV, or HCV infection or mothers who meet the
behavioral or nonbehavioral criteria for increased probability of infection (regardless of their HIV, HBV or HCV status) should also be identified as having an increased probability of HIV, HB V or HCV infection

. ( Category IB ) (Questions 3/4C)

7. Massive blood loss and intravascular volume replacement by infusion of crystalloid and colloid solution and transfusion of blood products can cause plasma dilution and result in unreliable test results fo r transmissible
infections. Donors should be considered at increased risk for harboring HIV, HBV and HCV when donor samples are determined to be diluted by an accepted plasma dilution algorithm and calculation method, such as provided by FDA, 13 d esigned to evaluate volumes administered in the 48 hours before specimen collection, even when no risk factors are identified. ( Category IB ) (Expert Opinion

- Question 3D)

Donor Screening

In recommendations 3 , 4 and 5 under Donor Screening, “the most sensitive test available” may include fourth generation antigen/ antibody tests , as these tests become available and are FDA

- licensed or approved for use in
the United States

. We include the above language in the recommendations should these types of tests be licensed or approved in the future.

1. Screening tests for HBV [ i.e., hepatitis B surface antigen ( HBsAg )

, antibody to hepatitis B core antigen ( a nti

- HBc ) ] , HCV (i.e., anti

- HCV), and HIV (i.e., anti

- HIV 1/2) should be performed on all potential organ
donors ( living or deceased) . ( Category I ) (Question 5A)

2. All prospective living donors should have serologic screening for HIV, HBV and HCV and NAT screening
for HIV and HCV as close to the time of organ recovery as feasible, but no longer than 7 days pre

- recovery. Test results should be obtained before organ recovery occurs , if feasible

. ( Category I )

3. Deceased p otential organ donors also should be screened f or HIV using NAT or the most sensitive test available regardless of risk of having HIV and regardless of time relative to procurement (i.e., D onor13

specimens should be obtained before procurement; however, NAT results should be obtained either before,
if timing allows, or after procurement). ( Category IB ) (Question 3A)

4. Deceased potential organ donors also should be screened for HCV using NAT or the most sensitive test available regardless of risk of having HCV and regardless of time relative to procuremen t (i.e., D onor specimens should be obtained before procurement ; however

, NAT results should be obtained either before, if timing allows, or after procurement). ( Category IB ) (Question 1B)

5. Deceased p otential organ donors reported to have behavioral or nonb ehavioral factors during the previous 12 months identifying them as being at increased risk for having HBV also should be screened with HBV NAT or the most sensitive test available, in addition to routine serologic testing and regardless of time
relative t o procurement (i.e., Donor specimens should be obtained before procurement; however, NAT
results should be obtained either before, if timing allows, or after procurement). (Refer to Table 3 for risk factors) ( Category IB ) (Question 3B)

6. When a deceased pot ential organ donor‟s behavioral/medical history questionnaire cannot be obtained or behavioral and nonbehavioral risk factors cannot be determined, donor NAT screening or the most sensitive test available for HBV should be performed . (Category IB ) (Questio ns 3/4D).

Table 3. Factors identified in the literature to be associated with increased likelihood of

recent HIV, HBV or HCV i nfection (See Appendix I for more detailed information )

● Sexual Contact

■ Persons who have had sex with ≥2 partners in the preceding 12 months

■ Persons who have had sex with a person known or suspected to have HIV, HBV or
HCV infection in the preceding 12 months

■ Men who have had sex with another man (MSM) in the preceding 12 months

■ Women who have had sex with a man with a histo ry of MSM behavior in the preceding 12 months

■ Persons who have had sex in exchange for money or drugs in the preceding 12
months

■ Persons who have had sex with a person who had sex in exchange for money or drugs in the preceding 12 months

■ Persons who have h ad sex with a person who injected drugs by intravenous, intramuscular, or subcutaneous route for non

- medical reasons in the preceding 12
months

● Birth to a mother infected with HIV, HBV or HCV (for infants ≤2 years of age)

● Persons who have injected drugs by intravenous, intramuscular, or subcutaneous route for

non

- medical reasons in the preceding 12 months

● Intra

- nasal use of an illicit drug (e.g., cocaine, heroin) in the preceding 12 months

● Inmate of a correctional facility (e.g., jail, prison, juvenile dete ntion) >3 consecutive days in the preceding 12 months

● Persons who have, or have been treated for, syphilis, gonorrhea, or genital ulcers in the preceding 12 months

● Persons who have been on hemodialysis in the preceding 12 months (for HCV only)

● Persons who have immigrated to the United States in the preceding 12 months from a country of intermediate or high hepatitis B prevalence (for HBV only)14 7. Only FDA licensed

- screening tests or approved

- diagnostic tests should be used to test blood samples from living o r deceased organ donors for HIV, HBV or HCV. ( Category I )

8. Since rates of infection transmission and recipient outcomes vary by organ, organ donor screening for
deceased donors should still be done even if results cannot be obtained before the organ is transplanted

, in
order to guide recipient management post

- transplantation. Specifically, screening results for HIV, HBV or HCV may be reported following organ transplantation in situations of life

- threatening illness where benefits of transplantation outwe igh potential risks of infection transmission. ( Category IB ) (Question 7J)

9. All donor (living or deceased) screening tests

, including diagnostic and confirmatory (if required), for HIV,
HBV and HCV should be performed as described in the package insert

. Testing by the conventional algorithm should be performed as early as possible, even if it follows the procurement of the organs. ( Category I )

HBV

- Infected Donors and Transplantation

For a non

- liver allograft, a presumed HBV

- infected donor is defined as being positive for HBsAg, IgM anti

HBc and / or HBV NAT. For a liver allograft donor, being positive for IgG anti

- HBc is also included.

A presumed HBV

- infected transplant candidate is defined as being positive for HBsAg

, IgM anti

- HBc

, and/or
HBV NAT. A candidate who is IgG anti

- HBc

- positive only could be a chronic carrier with HBsAg at an
undetectable level or could have cleared the virus.

1. Transplantation of a liver allograft from an HBV

- infected donor into an HBV

- infected transplant candidate may be co nsidered when risk

- benefit is considered favorable by the patient and transplant center

. (Category IIB) (Question 7A)

2. Transplantation of a liver allograft from an HBV

- infected donor into an HBV

- uninfected transplant
candidate should be avoided unless the risk to the recipient of not performing the transplant is elevated and deemed to be greater than the risk of disease development

. Should liver transplantation occur, s trategies to further minimize this risk should be considered (e.g., HBV vaccination of the transplant candidate; hepatitis B immune globulin

, and anti

- viral therapy). (Category IB) (Question 7B)

.

3. Transplantation of a non

- hepatic organ from an HBV

- infected donor into an HBV

- uninfected transplant candidate may be considered when risk

- benefit is considered favorable by the patient and transplant center

. (Category IIB) (Question 7C)

4. When allografts from HBV

- infected donors are utilized, transplant centers should obtain informed consent from the patient regarding the probability of HBV transmission and implement strategies to further
minimize the consequences of acquiring an HBV infect ion, as appropriate (e.g., HBV vaccination of the transplant candidate if a nti

- HBs negative; hepatitis B immune globulin

, and anti

- viral therapy)

. (Category IB) (Question 7D)

5. The use of a non

- hepatic organ from an IgG anti

- HBc positive only donor may be c onsidered for transplantation, as a positive IgG a nti

- HBc with negative HBsAg and negative a nti

- HBs is of unclear clinical significance; the probability of HBV transmission to the uninfected recipient is likely low; and graft/patient survival post

- transplantation is unknown. Strategies to further minimize this risk should be considered (e.g., HBV vaccination of the transplant candidate if a nti

- HBs negativ e; hepatitis B immune globulin

, and anti

- viral therapy). (Category IIB) (Question 7E)15 6. Testing with HBV NAT and ascertainment of IgM and IgG anti

- HBc status should be considered for total

a nti

- HBc positive only donors to better evaluate the HBV risk in the recipient post

- transplantation. (Category IIB) (Question 7F)

HCV

- Infected Donors and Transplantation

A presumed HCV

- infected donor or candidate is defined as being positive for anti

- HCV and/ or HCV NAT.

1. Transplantation of an organ from an HCV

- infected donor into an HCV

- infected transplant candidate may be
considered given that the ris k

- benefit appears favorable , as patient and graft survival appear to be similar to receiving an organ from an HCV

- uninfected donor. (Category IIB) (Question 7G)

2. Transplant ation of an organ from an HCV

- infected donor into an HCV

- uninfected transplant candidate should not be performed unless the risk to the recipient of not performing the transplant* is elevated and deemed to be greater than the probability of HCV transmissio n and risk of disease development

. ( Category IB) (Question 7H) * L ife

- threatening illness requiring transplantation when no other organs are available and no other lifesaving therapies exist.

3. When organs from HCV

- infected donors are utilized, transplant centers should obtain informed consent
from the patient regarding the probability of HCV transmission and implement strategies to detect new infection quickly by post

- transplant recipient testin g using HCV NAT at minimum and also evaluat ing for
the use of anti

- viral therapy. ( Category IB) (Question 7I)

Recipient Informed Consent

1. A shared decision

- making process between the prospective recipient and the listing clinician should start at
the time the patient is placed on the transplant waitlist . Patients should be counseled to consider potential risks of both accepting and rejecting specific types of organs from donors known to be infected with HBV or HCV; or donors at increased risk for HBV, HCV, or HIV infection . (Category IB) (Expert Opinion

– Question 1A)

2. Patients should be allowed opportunities to discuss with clinicians issues related to organ and associated risk acceptance at any time while on the waiting list. ( Category IB ) (Expert Opinion

- Question 1C)

3. At the time of the organ offer, the transplant center team primarily responsible for the patient‟s care should have a discussion with the prospective recipient that includes more specific information regarding the probability that this specific donor may trans m it HIV, HBV, or HCV based on the donor history and blood
test results available at that time to en able the potential recipient to understand the risk. Since vessel conduits may be transplanted from a different organ donor than the primary organ transplant, with different associated donor risks, an additional informed consent discussion by the transplan t center team may need to take place separately for the vessel conduit. ( Category I B ) (Expert Opinion

– Question 1D)

4. Transplant candidates should be informed that although all donors are screened for HIV, HBV, and HCV, there are limits to screening and no screening question or laboratory screening test can completely eliminate the risk for transmitting these infections. (Category IB) (Expert Opinion

– Question 1 E )16 Recipient Testing

1. Transplant candidates , for whom follow

- up testing is planned post

- transplant, should have a serologic assessment of their HIV, HBV, and HCV status at the time that they are admitted to the hospital to undergo the organ transplant but prior to implantation of the organ. (Catego ry IB) (Expert Opinion

- Question 2A)

2. Post

- transplant testing should be done for HIV, HBV, and HCV, unless infection has been documented pre

transplant, for all recipients of organs from living or deceased donors specifically when 1) recognized risk
facto rs place them at increased probability of acquiring donor

- derived HIV, HBV or HCV; 2) the donor screening specimens are hemodiluted; 3) a donor medical or social history is unavailable; or 4) the donor screening assay is repeatedly reactive. (Category IB) (Expert Opinion

- Question 2B )

3. Where the donor (living or deceased) was infected with HBV or HCV, post

- transplant recipient testing should be done, unless recipient infection has been documented pre

- transplant. (Category IB) (Expert Opinion

- Question 2C )

4. Recipient testing should be conducted for HBV , with respect to Expert Opinion 2B and 2C recommendations, at a minimum of 3 times at intervals of 1, 3 and 12 months post

- transplant and include screening for a nti

- HBs

, a nti

- HBc , and HBsAg (unless known through prior testing to be infected pre

transplant). (Category IB) (Expert Opinion

- Question 2D)

5. Recipient testing should be conducted for HIV with respect to Expert Opinion 2B and 2C recommendations,

at a minimum of 2 times at intervals of 1 and 3 months post

- transplant and include anti

- HIV

- 1 and 2 and
HIV NAT or test ing of equivalent sensitivity (unless known through prior testing to be infected pre

transplant). NAT or test ing of equivalent sensitivity is important for HIV detection as infected recipients may remain seronegative due to immunosuppression. (Category IB) (Expert Opinion

- Question 2E)

6. Recipient testing should be conducted for HCV with respect to Expert Opinion 2B and 2C recommendations, at a minimum of 2 times at intervals of 1 and 3 months post

- transplant and include HCV antibody and HCV NAT or test ing of equivalent sensitivity (unless known through prior testing to be infected pre

- transplant). NAT or test ing of equivalent sensitivity is important for HCV detection as infected recipients may remain seronegative due to immunosuppression. (Category IB) (Expert Opinion

- Question 2F)

Donor and Recipient Specimen Collection and Storage

1. For initial deceased donor screening, consider collect ing a separate ethylenediaminetetraacetic acid ( EDTA ) plasma specimens for NAT rather than using serum samples for serologic assays. When an alternate specimen is not available and a previously assayed serum is used for NAT, documentation should be provided. ( If only one specimen tube is feasible, a ll FDA licensed

- screening tests and/or FDA

- approved

tests are licensed for use with serum or EDTA plasma specimens

. ) (Category IIB) (Expert Opinion

- Question 3B)

2. For archival blood specimens, consider collecting two separate samples from all donors (living and deceased) and those recipients who receive organs from donors at increased risk for HIV, HBV, or HCV to reduce the possibility of specimen cross

- contamination. Ideally, one sample from ea ch individual of 10 ml
in a serum separator tube would be collected and processed to create 5 ml aliquots of serum for serologic testing. A second plasma sample of 3

- 5 ml collected in EDTA would be processed to create 1 ml aliquots for NAT. Smaller samples would be collected from pediatric donors and from pediatric recipients prior to17

implantation of the organ. Samples should be stored for at least 10 years. (If only one specimen tube is feasible, a ll FDA licensed

- screening tests and/or FDA

- approved tests are labeled for use with serum or EDTA plasma specimens

. ) (Category IIB) (Expert Opinion

- Question 3A)

3. When storage capacity exists and specimen volume permits, separating EDTA plasma samples that might be used for future NAT into multiple aliquots should be considered prior to long term storage as repeated
freeze

- thaw cycles can cause moderate reduction in viral nucleic acid levels

, with plasma samples maintained at approximately minus 70 o C. (Category IIB) (Expert Opinion

- Question 3C)

4. Storage of archival serum or plasma specimens for serology testing should be according to the test manufacturer‟s package insert. (Most manufacturers recommend long

- term storage at

- 20°C or colder.) (Category I)

5. Archival blood samples from prospective living donors should be drawn no longer than 7 days before organ recovery and stored for at least 10 years. ( Category I )

6. Infusion of crystalloid and colloid solutions and transfusion of blood products can result in false negative results for transmissible infections. Therefore, efforts should be made by the OPO to collect a qualified specimen; that is, a specimen that is deemed acceptable for testing according to an accepted plasma dilution algorithm and calculation method

, such as provided by FDA

. 13 (Category I)

7. All stored blood vessels from a donor found to be HIV, HBV, or HCV infected should be retrieved and quarantined immediat ely and either used only for research purposes or destroyed. (Category I)

Tracking and Reporting of HIV, HBV, and HCV

1. When reviewing medical records, OPO findings consistent with HIV, HBV, or HCV (e.g

. , mention of a positive test and/or risk factors for infection) in the deceased potential donor should be reported to the transplant center receiving the organ offer

. (Category I B) (Question 4A)

2. Any documentation of new infection in a recipient must be reported to the OPTN as required by policy and to appropriate local and state health departments as required by local and state law. (Category IC) (Expert Opinion

- Question 2H)

3. Data on the results of pre

- and post

- transplant bloodborne pathogen infection assessments in recipients
should be collected nationally and analyzed on a regular basis to inform policy decisions and future screening recommendations. Nationally aggregated data on donor

- derived infections should be disseminated to allow the transplant community to have access to the data. (Category IB) (Expert Opinion

- Question 2G)

4. Each institution involved in the procurement or storage of donor organs or blood vessels should have a graft
iden tification system that allows for tracking of organs and associated blood vessels from the donor source to the recipient institution and vice versa. Furthermore, each OPO should have mechanisms in place to
facilitate the communication between institutions for the purposes of tracking organs and blood vessels to recipients who should be notified if HIV, HBV, or HCV transmission from donor source material is suspected or confirmed. OPOs should keep accurate records of the distribution of each organ and associ ated
vessels. (Category I)18 5. The transplantation center should keep accurate records of all organs and blood vessels received and the disposition of each. Records of transplanted organs and blood vessels and stored blood vessels should be maintained in a place where this information i s easily accessible. Recorded information should include the organ type and blood vessels; donor identification number; name of OPO supplying the organ and blood vessels; recipient

- identifying information; and date of transplantation to the recipient or di scard date. (Category I)

6. If a transplant recipient is found to be newly infected with HIV, HBV, or HCV post

- transplant , the transplant center should, consistent with state law, immediately notify the state health department and the OPO from which the org an recovery originated. (Category IC)

7. Upon being notified that an organ recipient infected with HIV, HBV or HCV is suspected of being donor derived, the OPO should notify the OPTN and public health authorities where the affected donor organs

were recover ed ; the transplant center should notify the public health authorities that have jurisdiction where the affected recipient was transplanted . The procuring OPO, in collaboration with the state or local health department and with assistance from CDC, is respo nsible for determining as soon as possible whether the donor was infected. The investigation should include assessment of the HIV, HBV or HCV infection status of all recipients of those organs and tissues and performance of laboratory screening of any stor ed donor
material. (Category I C )

8. When HIV, HBV, or HCV infection is suspected or confirmed to be donor

- derived, the OPO should notify all transplant centers caring for recipients of that donor‟s organs and vessels, and institutions that recovered
tissues from the donor. (Category I)

9. Results of HIV, HBV and HCV screening test s for organ donors should be handled confidentially, in accordance with general medical practices and applicable federal and state statutes, regulations, and guidelines. (Category IC )

10. Prospective living donors should be notified if they are found through the screening process to be HIV,
HBV or HCV infected . (Category I)

11. Confirmed positive HIV, HBV or HCV test results in a prospective organ donor should be reported to state
health agencies by the OPO in accordance with state and local health department notification policies

. (Category IC)

12. Because of the possibility of sexual or parenteral transmission of infection, the spouse or known sex partners of deceased donors with HIV, HBV or HCV should be notified of their partner‟s infection status in
accordance with state law. Prior to notification of these persons, transplant and procurement organizations should be aware of their state and local health department notification policies. (Category IC)



## I II . Recommendations for Further Research

The systematic review uncovered numerous gaps in the literature affecting the ability to adequately address many of the ten key questions reviewed for this guideline. Additionally, many of the studies were not of sufficient quality to allow firm conclusions regarding certain interventions. In order to address identified gaps,
f uture studies should include the following to maximize impact : 1. P rimary analyt ic research methods19

2. Adjust ment for confounders
3. S tatistical power to detect significant differences
4. C linically relevant outcomes
5. C ontrols in both clinical and laboratory settings

The following are specific areas recommended for further research . Some of th e recommendations are also
listed as “n o recommendation/unresolved issue ” in the Evidence Review.

1. E stimate the incidence and prevalence of HIV, HBV and HCV among deceased potential organ donors
in the United States

. 2. T he risk

- benefit of transplanting organ s from HIV

- infected donors into HIV

- infected recipients, given the need for transplants in HIV

- infected recipients and improved outcomes with the availability of highly active anti

- retroviral therapy (HAART). However, prior to any research, legal analysis of the National Organ Transplant Act of 1984 [ 42 USC Sec. 273] and the HHS Final Rule [ 42 CFR Part 121] may be required, which obligate the OPTN to adopt standards that prevent recovery of organs from

HIV

- posi tive donors that result in a potential HIV transmission.
3. I dentify behavioral and non

- behavioral risk factors associated with increased incidence and prevalence of HIV, HBV, and HCV specifically among the potential organ donor population

, including pediatri c donors

. 4. Develop and implement a validated uniform donor infection risk assessment questionnaire.
5. Assess the validity of screening test results for HIV, HBV and HCV in relevant populations. This is also
needed to enable the calculation of useful statistic s including predictive values, likelihood ratios, and
post

- test probabilities of these tests among potential organ donors.

6. Evaluate fourth generation HIV and HCV antibody/antigen assays in transplant recipients and deceased organ donors for approval as licensed screening tests

. 7. Assess interventions (e.g., pathogen reduction methods) to reduce or eliminate the viral burden of HIV, HBV, and HCV in donor s or donor organs before or after recovery , but prior to transplantation

. 8. Evaluate outcomes of patients receiving HBV

- or HCV

- positive organs versus remaining on the transplant list, with statistical adjustment for relevant baseline characteristics and consideration of prophylaxis post

- transplant and patient race and ethnicity . More comprehensive analyses of competing risks would help inform critical decision making.
9. Evaluate transplant candidate and recipient outcomes if organ donors with behavioral or nonbehavioral risk factors were excluded from donating. This process may also require comparing incidence o f infection among population subsets within risk factors.
10. To better quantify risk based on behavior in a given donor, transplant centers may consider using a relative or comparative risk

- based quantitative process, such as a donor risk index, to allow the transplant center and patient to assess a donor based on level of risk for transmitting HIV, HBV, or
HCV. However, since data may be lacking for calculation of precise quantitative values, risk assessments in this guideline are qualitative, i.e., a donor i s categorized at increased risk or not at
increased risk
11. Evaluate the rate of false positive immunoassay and NAT results for HIV, HBV and HCV among potential organ donors and the percentage of cases where donors are declined due to such results
stratified by organ type.
12. D evelop standardized algorithms for real

- time discrimination of initially reactive organ donor NAT
results to separate true versus false positive results.
13. I dentify the limits of acceptable plasma dilution. Plasma dilution algorithms and calculation methods are not standardized for organ donors and the limits of acceptable plasma dilution have not been validated across HIV, HBV and HCV serological assays used for organ donors. In addition, e valuate the effect of20

analyte movement from the v ascular compartment during and immediately following introduction of crystalloids or colloids to the vascular system

. 14. For transplant candidates who are HBV

- uninfected and receive a non

- hepatic organ from an HBV
infected donor who is anti

- HBc positive onl y, evaluate transmission rates where IgM and IgG testing is performed and various prophylaxis measures , including vaccination, are used in order to improve knowledge on best practices to minimize transmission risk.



## I V. Scope and Purpose

This guideline s upplants the 1994 PHS Guidelines for Preventing Transmission of HIV through Transplantation of Human Tissue and Organs

. 1 The revised guideline includes specific recommendations for implementation.
Recommendations for further research are also i ncluded to address the knowledge gaps in HIV, HBV and HCV transmission prevention, detection, and management identified during the literature review and through expert opinion.

The major changes to the guideline are :

● Addition of HBV and HCV, in addition t o HIV.

● Utilizing the factors known to be associated with increased likelihood of recent HIV, HBV or HCV to identify potential donors at increased risk for transmitting infection versus exclusionary criteria for
donation.

● Focusing on solid organs from dece ased and living donors since the Food and Drug Administration 13 has since implemented more comprehensive regulations of tissues and semen donors.

● Distinguishing between expe cted and unexpected transmission of HBV and HCV

. In the future this guideline may apply to vascularized composite allotransplantation (the transplantation of multiple tissues as one unit, such as a limb or face ) depending on regulatory decision making concerning the definition of an organ

.

This document is intended for use by OPO staff; transplant staff including physicians, nurses, administrators, and clinical coordinators; and laboratory staff responsible for testing and storing donor and recipient specimens; and persons responsible for developing, implementing, and evaluating infection prevention and control programs for organ procurement organizations and transplant centers.

To evaluate the evidence on reducing transmission of HIV, HBV and HCV, we examined data addressing ten key questions within five major topic areas. A sixth topic area includes questions addressed by Expert Opinion (EO)

. We drew upon expert s to draft summaries related to th ese questions anticipating that a systematic review of the literature would produce insufficient evidence

- based data

. The summaries were written and edited by the guideline authors

.

Table 1

. Questions for Systematic Review

Major topic area of the guideline Question for Systematic Review

I. Probability of transmission of HIV, HBV, or HCV through solid organ transplantation (SOT) 1. What are the prevalence and incidence rates of HIV, HBV, and HCV among potential solid organ donors?

2. What are the rates of transmission to recipients from don ors infected with HIV, HBV, or HCV? Do the rates vary by the organ transplanted or when the donor was infected?21 Major topic area of the guideline Question for Systematic Review

II. Method ology to better estimate donor infection with HIV, HBV, or
HCV 3. What behavioral risk factors are associated with an increased probability of infection with HIV, HBV, or HCV? What is the prevalence of these characteristics among potential solid organ donors?

4. What nonbehavioral factors are associated with an increa sed probability of infection with HIV, HBV, or HCV? What is the prevalence of these factors among potential solid organ
donors?

5. What are the test characteristics of the screening methods available to detect HIV, HBV, and HCV in potential solid

organ donors? Do test characteristics differ in particular populations and with donor clinical status (i.e., donation
after brain death v ersus donation after cardiac death OR adult vs. pediatric donors)?

III. Donor interventions to decrease transmission of HIV, HBV, or HCV
from infected donors 6. Which donor interventions reduce the probability of pathogen transmission from an organ donor infected with HIV, HBV, or HCV to a previously uninfected recipient?

IV. Potential risks and benefits of transplanting, or n ot transplanting, solid organs from donors positive
for HIV, HBV, or HCV 7. How do the clinical outcomes of recipients of organs from donors infected with HIV, HBV, or HCV compare to those who remain on the transplant list?

V. Potential risks and benefits of transplanting, or not transplanting, organs from donors with risk
factors for HIV, HBV, or HCV 8. How do the clinical outcomes of transplant recipients who receive organs from donors with behavioral or
nonbehavioral risk f

actors compare to those who remain on the transplant list?

9. What is the impact of excluding potential solid organ donors with behavioral or nonbehavioral risk factors on the organ donor pool?

10. What is the impact of false positive tests on the organ donor pool?

VI. Approaches to informing recipients
about the risk s of HIV, HBV, and
HCV transmission and evaluat ion for possible exposure post

transplantation

Note: The related three questions were not part of the systematic literature
review. EO1. How and when should informed consent be obtained from potential recipients to help them consider the risks (i.e., probability of acquiring the disease and consequences of disease acquisition) of donor

- derived HIV, HBV, and HCV?

EO2. When should testin g of a transplant recipient be done to
detect HIV, HBV, and HCV transmission from the donor?

EO3. How should donor and recipient specimens be collected and stored for potential investigation of donor

- derived HIV, HBV, and HCV infection?22 

## V. Background

Federal Oversight of Organ Recovery and Transplantation

Several federal agencies either regulate or oversee procurement and transplantation of organs. These activities range from the publication of PHS guidelines that address the transmission of communi cable diseases through transplantation to regulatory re quirements. The Health Resources and Services Administration (HRSA) provides oversight of solid organ transplantation through the OPTN

, established by Congress under the National Organ Transplant Act of 1984. Public Health Service Act 42 CFR. P art 121, requires t he OPTN be
administ rat ed by a private, non

- profit entity ; through a contract overseen by HRSA

, t he United Network for Organ Sharing is the entity that operates the OPTN. Th e Centers for Medica re and Medicaid Services
establishes performance standards and conducts surveys of transplant centers [ 42 CFR Parts 405, 482, 488, and 498] and OPOs [ 42 CFR Parts 413, 441, 486 and 498] to determine certification or recertification. Cur rently,
there are 58 OPOs and 253 organ transplant centers in the United States

.

HIV, HBV, HCV and Organ Transplantation Transplantation of solid organs, including kidney, heart, liver, lung, pancreas, and intestine, to patients with end stage organ disease is performed to improve their survival and functional capacity. Organs can be donated by living or deceased donors with a majority of organs recovered from heart beating, deceased donors. Transplantation rates differ by organ. Kidney transplantation occurs most often followed by liver, heart, lung, kidney

- pancreas, intestine, and heart

- lung. On average, three organs are re covered from each deceased donor. In
2010 , 28, 662 patients on the United Network for Organ Sharing (UNOS) transplant waitlist received organ transplants from 7,943 deceased donors and 6,564 living donors in the United States

. 14

There is currently a significant discrepancy between the number of candidates on the transplant list and the limited number of organs available with thousands of patients on the waitlist dying annually. To narrow this gap and given the urgency of organ transplantation, attempts have been made to increase the organ donor pool by
includi ng expanded criteria donors; and donors who may either be at increased probability of harboring transmissible infections including HIV, HBV, or HCV.

Donor

- Derived Infections In a study of 13,66 7 potential organ donors evaluated January 2004 to mid

- 2008 by 17 OPOs , the prevalence of

HIV and HCV in normal

- risk donors was 0.1 0 % and 3.45 % , respectively ; the prevalence of HIV and HCV among potential donors identified by OPOs as “high risk” was 0. 50 % and 18. 20 % , respectively. The 17 OPOs
recover more than half o f the organ donors in the United States. Blood screening tests that produce nucleic acid test (NAT)

- positive, antibody

- negative serologic results are indicative of recent, or incident, infections. Applying a model based on known prevalence, the estimated i ncidence of undetected viremia for normal

- risk potential donors was 1 in 50 ,000 for HIV and 1 in 5,000 for HCV . For high

- risk potential donors, the incidence
of undetected viremia was 1 in 11,000 for HIV and 1 in 1,000 for HCV

. 15 In a 2008 surve y of the 58 OPOs, approximately one

- half performed HIV and HCV NAT for all donors and one

- fourth perform ed HBV NAT

. 16

In 2005, the Organ Procurement and Transplantation Network (OPTN) p olicy required OPOs and tr ansplant centers to report suspected, unexpected donor

- derived infections to UNOS. The results from 2005

- 2007 are available, although underreporting may have resulted in an underestimation of the true incidence. Of 80 potential donor

- derived disease transm issions reported to UNOS, 30 cases were confirmed. HIV, HBV and HCV were among the top five most reported suspected donor

- derived transmissions, although further testing of stored donor specimens were negative using NAT in most cases. 1723 Expected versus Unexpected Donor

- Derived Inf ection

Donor

- derived infections are differentiated into expected vs. unexpected transmission. Expected transmission is a common occurrence in organ transplantation. Given the large disparity between the need and availability of solid organs and that certai n organ transplants are life saving, it has become acceptable medical practice that certain infections may be transmitted in organ transplantation. When routine screening tests detect the infection in the donor, OPTN policy requires potential recipients to be informed of the risk prior to transplantation

. 18 Preventive strategies are offered, if available, to the recipient post

- transplantation. In contrast, unexpected transmission occurs when the pathogen was not detected prior to transplantation , with or without screening for
the infectious disease.

Expecte d HBV and HCV Donor

- Derived Infection Transplantation of organs from HBV

- and HCV

- infected donors is accepted medical practice. These organs are typically offered to recipients known also to be infected with the same pathogen, or in rare circumstances, to uninfected recipients in cases of urgent medical need where benefit is deemed to outweigh risks. In these situations, prophylaxis or treatment with immunizations, anti

- virals and/or immunoglobulin is offered if appropriate to prevent transmission or reduce the disease severity. Post

- transplant recipient testing is also
critical.

Unexpected HIV, HBV and HCV Donor

- Derived Infection Reports of unexpected HIV, HBV and HCV transmission have occurred when screening could not identify
donor infection. Most commo nly, this happens when a donor becomes infected with the virus close to the time of organ donation. There is an initial period of time after exposure, called the eclipse phase, during which viral replication occurs in target cells

. 19

, 20 The primary site for HIV is the CD 4 + lymphocytes located in gut

associated lymph nodes

. 21 Hepatitis virus replication is mainly confined to hepatocytes in the l iver. During this eclipse phase, plasma viremia is not detectable n or thought to be transmitted through blood transfusion ; h owever, the virus can be transmitted through infected organs. At the end of the eclipse phase, low concentrations of virus begin to circulate in the blood, but are not detectable by NAT until the ramp

- up phase,
identified as an exponential increase in virus. 20 Viral production eventually plateaus and is followed by a
decline due to the formation of antibod ies , which may be days or weeks after commencement of the ramp

- up phase

. 22 In addition to the window period between exposure and the ability of certain assays to detect infection,
false

- negative test results can occur for other reasons (e.g., hemodilution of the donor sample from blood transfusions).

The window period between viremia and detection of viral material or antibodies can vary depending on the particular virus, the sensitivity of the test used, and possibly the initial viral load at the time of inoculation. For individual donor NAT screening, HIV detection is estimated to be 5

- 6 days after the onset of viremia with a

sm aller window period of 3

- 5 days for HCV. Antibody detection of HIV is estimated to be 19

- 20 days after the onset of viremia for HIV and ranging from 58

- 65 days for HCV. 19

, 22

, 23 For HBV, the window period for viral
detection is much longer compared to HIV and HCV with estimates ranging from 20

- 25 days with indi vidual
donor NAT screening and 36

- 44 days to detection of HBsAg. 22

, 24

In 1986, two transplant recipients acquired HIV from the same donor. The organ donor initially tested HIV antibody negative after receiving a large number of transfusions. However, a blood specimen collected two days later at the time of organ recovery teste d HIV antibody positive. 3 In 2007, simultaneous transmission of HIV and HCV occurred in four organ recipients from the same donor who was identified as high risk due to a reported history of engaging in MSM behavior. Routine donor screening results were negative for HIV and
HCV antibodies. Ten months after transplantation, a kidney recipient tested positive for HIV and HCV

. Subsequently , the heart, liver and other kidney recipient tested positive for HIV and HCV, and an a r chived donor specimen tested positive for HIV and HCV by NAT. 11 In 2009, a liver transplant recipient who was24 HCV

- seronegative prior to surgery inadvertently received a stored vessel conduit from a n HCV

- seropositive
donor and tested HCV

- positive post

- transplant

. The transplanted liver and vessel conduit were from t wo different donors. Transplant centers are allowed to store donor vessel conduits up 14 days after recovery for use in transplant patients experiencing surgical complications

. 9 In 2009

, a kidney recipient acquired HIV from a living donor transplant. The donor had a history of engaging in MSM behavior, but tested HIV

- negative by EIA approximat ely 2 months before organ recovery. One year post

- recovery, the donor tested HIV

- positive. Store d recipient specimens collected 11 days pre

- transplant and 12 days post

- transplant were tested by HIV NAT with the post

- tran s plant specimen confirmed positive. A stored donor specimen collected 11 days pre

- tran s plant was

HIV NAT

- positive

. 10

Current Guidelines and Regulations Several guidelines and regulations have been implemented to decrease the risk of unexpected donor

- derived HIV, HBV, and HCV. The National Organ Transplant Act, passed by the US Congres s in 1984, established the
OPTN. The Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) administers the OPTN contract to oversee solid organ transplantation in the United
States , through a contract with UNOS. A total of 58 OPOs and approximately 2 52 transplant centers are
members of the OPTN. As members of the OPTN , transplant centers and OPOs agree to comply with the HHS Final Rule and policies.

Transplantation of Organs from HIV

- , HBV

- , HCV

- Infe cted Donors OPTN policy recommends that “organs from donors with a positive screening test or confirmed medical condition that may be transmittable, with the exception of HIV, may be transplanted at the discretion of the transplanting program with the info rmed consent of the recipient

. ” 18

Screening of Donors OPTN policy lists the minimum procurements standards for an OPO in evaluating deceased donors, which includes obtaining a donor history, reviewing the medical chart, obtaining vital signs, performing a physical examination, and performing pertinent laboratory tests including FDA

- licensed anti

- HIV I/II and hepatitis serologic testing

. 25 Currently, there are no OPTN policies that address screening of living donors. Instead, transplant programs that perform living donor transplants are required to develop protocols for medical evaluation of potential living donors to include screening for evidence of transmissible diseases. Approved guidance documents have been developed to aid this process. 26 OPTN policy defines a potential donor as

“ increased risk” 25 if he/she meets any of the exclusionary criteria in the 199 4 PHS Guidelines for Preventing Transmission of HIV through Transplantation of Human Tissue and Organs

.

In 1994, the PHS released Guidelines for Preventing Transmission of HIV through Transplantation of Human Tissue and Organs

, 1 which included do nor exclusionary criteria. Currently, p otential blood and tissue donors who have risk factors for bloodborne pathogen infection, such as HIV, are excluded from donating, since the availability of blood and tissue exceeds supply. In contrast, organs may be considered life

- saving and since
demand far exceeds demand , “ increased risk” donors are not excluded but can be accepted by transplant centers if patients are informed of the risks involved and consent

. 18 Currently, OPTN

- defined “ increased risk” criteria, originally developed only for HIV, have been expanded by many OPOs to assess risk for other infections, including HBV and HCV. A recent OPO survey found that the percentage of recovered organ donors wh o were reported as having “ increased risk” behaviors varied among these organizations from a range of 2.3% to 26.1%
of annual donor volume. 16

Screening of Recipients Prior to transplantation, HIV

, HBV and HC V screening is required by OPTN policy unless this practice violates specific laws or regulations

. 18 Transplant centers may choose to evaluate candidates for additional infections to25 determine suitability for p lacement on the transplant waitlist. Candidates who test positive for HIV may be placed on the waitlist if judged to be medically appropriate by the transplant center.

Since donor

- derived infections can result in substantial morbidity and mortality, parti cularly when there is a delay in diagnosis, the 1994 PHS Guidelines recommended recipients be tested for HIV immediately prior to transplantation and at 3 months post

- transplant until the risk of HIV transmission from organ donors was clarified by future s tudies. However, testing recipients who receive organs from “ increased risk” donors is not required by OPTN policy, and data have shown it is not standard practice. 27 Benefits of routine testing in these situations include early identif ication of infection and treatment before signs and symptoms develop, as well as early notification of organ recipients from the same donor should the donor be a suspected source.

Reporting In 2005, OPTN policy was revised to require OPOs and transplant centers to report potential donor

- derived
infections to the OPTN. 18 When an organ recipient is suspected of having a donor

- derived infection, UNOS and all institutions that recovered or transplanted organs from the donor are notified. In most instances an investigation ensues with testing of stored donor serum and recipient specimens in order to determine the infection source and provide information to facilitate medical treatment decisions. Current standards by the Association of Organ Procurement Organization (AOPO) require donor serum be maintained for 10 years following procurement of organs. HIV, HBV or HCV are nationally notifiable diseases and confirmed infections require notification to local or state hea lth agencies, as stipulated. All cases are reviewed by the
OPTN Ad Hoc Disease Transmission Advisory Committee (DTAC) to determine the likelihood of the donor being the source of infection. 17

Available Screening Tests OPTN policy requires deceased donor screening for anti

- HIV, HB sAg, anti

- HBc, and anti

- HCV. An FDA

licensed screening test is required for anti

- HIV. FDA

- licensed, approved or cleared serologic a l screening tests are required for HBV and HCV; however, an FDA

- licensed, approved or cleared diagnostic test is permitted when an FDA screening test is unavailable

. 25

The FDA has licensed several HIV, HBV, and HCV screening tests, including enzyme immunoassays (EIAs) that detect antibodies to the virus, antigen assays

, and NAT. Each generation of serologic test has decreased the window period for detection of infection. The FDA determines if t hese assays can be use d on either fresh or frozen samples of serum or plasma and if approved for use in living or cadaveric (pos t

- asystole) donors. Blood samples are recovered pre

- asystole from potential donors after they are pronounced dead by neurological
criteria and also from donation after circulatory death donors pre

- asystole

. Fourth generation tests, which are
combined antib ody

- antigen tests, have recently been developed for HIV and HCV. The FDA

- approved HIV antigen

- antibody test can be used in blood donor screening under urgent circumstances when licensed tests are unavailable or impractical for the circumstances. The HCV fo urth generation assay application for FDA licensure or approval for use in the United States has not occurred.

Although there are minimum standards on organ donor screening, actual screening protocols vary. The serologic tests used differ based on the OPO . In addition, the use of NAT for HIV, HBV and HCV screening varies significantly. NAT has received increased attention given the potential for false negative results during the window period before antibodies develop . However, there are also concerns with NAT including the lack of
standardization in algorithms on an initial positive result ; potential for false positive results if testing is not performed in a well

- controlled lab or testing volume is low 28 ; and feasibility/turn

- around time. Approximately
50% of OPOs perform HIV and HCV NAT on all potential donors compared to 25% for HBV NAT. Of the OPOs that use NAT, 45% send the sp ecimens to a different state where 24/7 NAT screening is available. Other OPOs reported using on

- site locations, transplant center laboratories, and outside labs within the same state. 1626 

## VI. Methods

This gui deline was based on a targeted systematic review of the best available evidence on preventing transmission of HIV, HBV, and HCV through solid organ transplantation. We used an adapted Grading of Recommendations Assessment, Development and Evaluation (GRADE ) approach 12

, 29

- 32 to provide explicit
links between the avai lable evidence and the resulting recommendations. Our guideline development process is
outlined in Figure 1.

Figure 1. The Guideline Development Process27 Development of the guideline involved participations of three groups. The Working Group included members
of the CDC Office of Blood Organ and Other Tissue Safety in the Division of Healthcare Quality Promotion ; Center for Evidence

- based Practice at the University of Pennsylvania Health System; and the ECRI Institute
Evidence

- based Practice Center . The Working Group was accountab le for all phases of guideline methodology, including development of key questions, the evidence report, and the guideline itsel f, as well as providing the Expert Panel and Review Committee with progress updates

. The Expert Panel comprised individuals with subject matter expertise in HIV and hepatitis; assistance was sought from various members of the Expert Panel to address specif

ic issues throughout development of the guideline. The Review Committee was formed to provide stakeholder input from a public health, regulatory, and transplantation infectious disease perspective for the topics addressed in the guideline, as well as contr ibution from manufacturers of infectious disease tests. Both the Expert Panel and Review Committee participated in regular progress updates via conference calls at key steps and provided review and feedback on the key questions, bibliography resulting from the literature review, evidence report and guideline.



## Development of Key Questions

We first conducted an electronic search of the National Guideline Clearinghouse, MEDLINE, EMBASE, and the Cochrane Health Technology Assessment Database, and contacted ex perts to identify existing national and international guidelines and reviews relevant to HIV, HBV, and HCV transmission in solid organ
transp l antation. A preliminary list of key questions was developed from a review of the relevant guidelines and
reviews i dentified in the search. Key questions were put in final form after vetting them with the Expert Panel
and Review Committee

. An analytic framework depicting the relationship among the key questions is included
in Figure 2

.28 Figure 2 .Analytic Framework



## Literature Search

Following the development of the key questions, search terms were developed for identifying literature most relevant to those questions. For the purposes of quality assurance, we compared these terms to those used in
relevant seminal studies and reviews

. These search terms were then incorporated into search strategies for the relevant electronic databases. Searches were performed in MEDLINE, EMBASE, the Cochrane Library, DARE, HTA, NHS EED, and Healthcare Standards and last updated June 30, 2009. R esulting references were imported into a citation management database where duplicates were resolved. Mechanisms used to retrieve additional relevant information included review of bibliographies/reference lists from peer reviewed and gray literature (gray literat ure consists of reports, studies, articles, and monographs produced by federal and local government agencies, private organizations, educational facilities, consulting firms, and corporations; these documents do not appear in the peer

- reviewed journal lite rature). The detailed search strategy used for identifying primary literature can be found in the evidence report Solid Organ Transplantation and the Probability of Transmitting HIV, HBV, or HCV: A Systematic Review to Support an Evidence

- based Guideline

.29 

## Study Selection

Titles and abstracts from references were screened by a single reviewer (JT or MN from ECRI ). Full text articles were retrieved if they were relevant to one or more key questions, and met inclusion criteria. These
criteria included uni versal as well as question specific criteria. Universal criteria included studies that were 1) written in the English language, 2) peer

- reviewed, full length publications with original data, and 3) included HIV, HBV, or HCV with determination of the infect ion based on laboratory test(s) rather than subjective estimates, physician interviews, or patient interviews. Additional criteria applied on a per

- question basis are depicted in Table 4

.

Multiple publications of the same study were treated as a single s tudy rather than as multiple studies to avoid
double

- counting patients. Full

- text articles were screened by two independent reviewers (JT and MN) and disagreements were resolved by discussion. The results of this process are depicted in Figure 3. To ensure that all relevant studies were captured in the search, the bibliography was vetted by the Expert Panel and Review
Committee

.

Table 4

. Question

- Specific Inclusion Criteria

Inclusion Criteria * Questions for Systematic Review

1 2 3 4 5 6 7 8 9 10

Pertinent data on at least five people         

Data collected in U

. S

. A

.    

Rates not restricted to actual donors 

At least one of four populations: 1) Potential organ donors; 2) organ donors with samples taken prior to 1992 that were retrospectively tested for HCV; 3) potential tissue donors; or 4) the general population (for this last population, we included only the most up

- to

- date epidemiological estimates) 

Regardless of ex h ibiting symptoms for HIV, HBV or HCV  

Donor seropositive pre

- transplant   

Recipient seronegative pre

- transplant 

Single type of organ, or separated data on different types of organs   

Waitlist control OR Control is recipients of organs from uninfected donors 

If pre

- transplant infected recipients and pre

- transplant uninfected recipients were included, the study must have reported separate outcome data on these two types of recipients

. 

Reported patient survival, graft survival, or quality of life

.  

At least one of four populations, enrolling individuals of any age: 1) Potential organ donors; 2) potential tissue donors; 3) potential blood donors; or 4) a sample representative of the general population (i.e., population unselected for any particular demographic, occupational, or behavioral characteristics, or health status other than HCV, HBV, or HIV infection status)  30 Inclusion Criteria * Questions for Systematic Review

1 2 3 4 5 6 7 8 9 10

A study of a specific demographic or socioeconomic subpopulation was included for HBV, but excluded for HIV and HCV

.  

A study of a specific subpopulation of patients who were all selected for having the same behavioral risk factor was excluded for all three pathogens

.  

Article must have been published in 1990 or later if pertinent to HIV or HCV, or 1966 or later if pertinent to HBV

.  

In order to identify risk factors for the pathogen, study must have enrolled people with the risk factor as well as people without the risk factor; similarly, the study must have enrolled people positive for the pathogen as well as people negative for the pathogen

.  

For identification of clinical signs and symptoms that may indicate infection, data may be from any country. For identification of co

- morbidities or demographic factors that may be associated with infection, data must be from U.S only. 

Reported at least one of the tests listed in Table 5

. 

Reported at least one of the following:

● Sensitivity and specificity

● Positive and negative predictive values (clinical populations only)

● Positive and negative likelihood ratios (clinical populations only)

● Sufficient data to calculate the above

● Window period

● Turnaround time 

Reported data on an individual test basis rather than multiple tests or algorithms

. 

Inactivation procedure performed before transplant on organs obt ained from infected individuals. 

Donor positive pre

- transplant for behavioral risk factor or signs/symptoms
risk fa ctor or comorbidity risk factor. 

Waitlist control OR Control is recipients of organs from donors without that
risk factor

. 

Reported the number of organs that would not be included in the organ pool if donors with behavioral or nonbehavioral risk factors identified in questions 3 and 4 were excluded. 

Reported the number of organs that would not be included in the organ pool if false positives were excluded

. 

* For each Question for Systematic Review, five universal criteria were also applied (see text above ). A checkmark in a given column means that a study must have met that criterion in order to be included for the numbered Question for Systematic Review.

The specific tests of interest for Question 5 are listed in Table 5. For the systematic review of the literature, t ests of interest include d immunoassay s and NAT currently used in the United States by OPOs ; fourth

- generation HIV and HCV antibody/antigen tests currently in use outside of the United States also were included

. Other

FDA

- licensed assays not i ncluded in the literature review and identified as not routinely used by U.S. OPOs are indicated with an asterisk

.31 Table 5

. Tests of Interest for Question 5

Virus Test Name Manufacturer Use

Tests Currently Available for Use by U

. S

. Organ Procurement Organizations

HIV

anti

- HIV

- 1/2 (detects
antibodies to HIV

- 1, HIV

- 2 and if applicable HIV

- 1 group 0) Genetics System (GS) HIV

- 1/HIV

- 2 Plus 0 EIA Bio

- Rad Laboratories FDA licensed for donor screening

HIVAB HIV

- 1/HIV

- 2 (rDNA) EIA Abbott Laboratories FDA licensed for donor screening

Abbott PRISM HIV 0 Plus * Abbott Laboratories FDA licensed for donor screening

HBV
HBsAg (detects Hepatitis B surface antigen) Abbott PRISM H B sAg Assay Abbott Laboratories FDA licensed for
donor screening

Genetic Systems (GS) HBsAg EIA 3.0 Bio

- Rad Laboratories FDA licensed for donor screening

Auszyme Monoclonal * Abbott Laboratories FDA licensed for donor screening

ADVIA Centaur H B sAg Assay Siemens Healthcare Diagnostics FDA a pproved for diagnosis

AxSYM HBsAg Abbott Laboratories FDA a pproved for diagnosis

HBV

anti

- HBs (detects
antibodies to the surface antigen) Ausab EIA Abbott Laboratories FDA licensed for donor screening

HBV

anti

- HBc (detects
antibodies to the core antigen) Abbott PRISM HBcore Abbott Laboratories FDA licensed for donor screening

CORZYME Abbott Laboratories FDA licensed for donor screening

Ortho HBc ELISA Test System Ortho Clinical Diagnostics FDA licensed for donor screening

ADVIA Centaur HBc Total Assay Siemens Healthcare Diagnostics FDA a pproved for diagnosis

AxSYM Core 2.0 Abbott Laboratories FDA a pproved for diagnosis

HCV

anti

- HCV (detects antibodies to HCV) Abbott HCV EIA 2.0 Abbott Laboratories FDA licensed for donor screening

ADVIA Centaur Anti

- HCV Siemens Healthcare Diagnostics FDA a pproved for diagnosis

AxSYM Anti

- HCV Abbott Laboratories FDA a pproved for diagnosis

Ortho HCV Version 3.0 ELISA Test System Ortho Clinical Diagnostics FDA licensed for donor screening

Abbott PRISM HCV* Abbott Laboratories FDA licensed for donor screening

HIV

- 1, HCV and HBV NAT
(detects HIV

- 1 and HCV RNA and HBV DNA) Procelix Ultrio* Gen

- Probe , Inc. FDA licensed for donor screening

COBAS TaqScreen MPX Test* Roche Molecular Systems, Inc FDA licensed for donor screening32

Virus Test Name Manufacturer Use

HIV

- 1 and HCV NAT (detects HIV

- 1 and HCV RNA) ProCleix HIV

- 1/HCV Gen

- Probe , Inc. FDA licensed for donor screening

HIV

- 1 NAT
(detects HIV

- 1 RNA) COBAS AmpliScreen HIV

- 1 Test v. 1.5 Roche Molecular Systems, Inc FDA licensed for donor screening

HCV NAT
(detects HCV RNA) COBAS AmpliScreen HCV Test v. 2.0 Roche Molecular Systems, Inc FDA licensed for donor screening

HBV NAT
(detects HBV DNA) COBAS AmpliScreen HBV Test Roche Molecular Systems, Inc. FDA licensed for
donor screening

Fourth Generation Tests (currently not in use in U.S. Organ Procurement Organizations)

HIV
(detects HIV

- 1 p24 antigen
and antibodies to HIV

- 1, groups M and O, and/or
HIV

- 2) ARCHITECT HIV Ag/Ab Combo Abbott Laboratories FDA licensed for diagnosis

AxSYM HIV Ag/Ab Combo Abbott Laboratories Not FDA licensed, approved or cleared

COBAS Core HIV Comb i Roche Diagnostics Not FDA licensed, approved or cleared

Enzygnost HIV Integral II Siemens Healthcare Diagnostics Not FDA licensed, approved or cleared

Genscreen Plus HIV Ag/Ab Combo Bio

- Rad Laboratories Not FDA licensed, approved or cleared

Genscreen HIV Ultra Ag / Ab Assay Bio

- Rad Laboratories Not FDA licensed, approved or cleared

Murex HIV Ag/Ab Combo Abbott Laboratories Not FDA licensed, approved or cleared

Modular E170 HIV Comb i Roche Diagnostics Not FDA licensed, approved or cleared

VIDAS DUO ULTRA bioMerieux Clinical Diagnostics Not FDA licensed, approved or cleared

VIDAS DUO QUICK bioMerieux Clinical Diagnostics Not FDA licensed, approved or cleared

Vironostika HIV Uni

- Form II Ag/Ab bioMerieux Clinical Diagnostics Not FDA licensed, approved or cleared

HCV

anti

- HCV (detects antibodies to HCV) INNOTEST HCV Ab IV Innogenetics NV Not FDA licensed, approved or cleared

Murex 4.0 Abbott Laboratories Not FDA licensed, approved or cleared

HCV
(detects HCV antigen and antibodies to HCV Monolisa HCV Ag/Ab Ultra Bio

- Rad Laboratories Not FDA licensed, approved or cleared

EIA or ELISA

– Enzyme

- linked immunosorbent assay
NAT

– Nucleic acid test
*FDA

- licensed assays identified as not routinely used by U.S. OPOs and not included in the literature review33 Figure 3. Study Flow Diagram



## Data Extraction and Synthesis

For those studies meeting inclusion criteria, data were extracted by a single author (JT or MN from ECRI ). Disagreements were resolved by the remaining authors. Data and analyses were extracted as originally presented in the included studies. For the purposes of our review, statistical significance was defined as p ≤
0.05.34 

## Grading of Evidence

First, the quality of each study was assessed using the quality assessment criteria (adapted from existing methodology checklists) listed in Table 5 of the Evidence Report. Next, the quality of the evidence base was assessed using methods adapted from the GRADE Working Group. In summary, GRADE tables were developed for each of the interventions or questions addressed within the evidence tables. Included in the GRADE tables were the intervention of interest, any outcomes listed in the evidence tables that we re judged to be clinically important, the quantity and type of evidence for each outcome, the relevant findings, and the GRADE of evidence for each outcome, as well as an overall GRADE of the evidence base for the given intervention or question.

The init ial GRADE of evidence for each outcome was deemed high if the evidence base included a randomized
controlled trial (RCT) or a systematic review of RCTs, low if the evidence base included only observational studies, or very low if the evidence base consiste d only of expert opinion or uncontrolled studies. The initial GRADE could then be modified by eight criteria. Criteria that can decrease the GRADE of an evidence base include shortcomings in quality, consistency, directness, or precision and publication bi as (e.g., Was the funding for this study derived from a source that would not benefit financially from either data favorable to the test or data unfavorable to the test?) . Criteria that can increase the GRADE include a large magnitude of effect, a dose

res ponse gradient, or inclusion of unmeasured confounders that would increase the magnitude of effect and are
listed in Table 6 . Studies equivalent to RCTs (e.g., a controlled study not requiring randomization, like a study in genetically identical mice) woul d also start out as high level evidence, but would often lose points for
indirectness. For questions regarding prevalence

, incidence or rates of transmission from donors to recipients, no randomized trials were necessary to address the questions. Therefore the starting evidence grade was High, and we applied the other components of the GRADE system as appropriate.

Table 6 : Rating the Quality of Evidence Using the GRADE Approach

Type of Initial Criteria to Decrease Criteria to Increase Overall Quality
Evidence Grade Grade Grade Grade

RCT → High

Observational → Low study

Any other

e vidence → Very (e.g., expert low opinion) Quality Serious (

- 1 grade) or very serious (

- 2 grades) limitation to study quality

Inconsistency Important inconsistency (

- 1 grade)

Indirectness Some (

- 1 grade) or major (

- 2 grades) uncertainty
about directness

Imprecision Imprecise or sparse data (

- 1 grade)

Publication bias High risk of bias (

- 1 grade) Strong association Strong (+1 grade) or very strong evidence
of association (+2 grades)

Dose

- response Evidence of a dose

response gradient (+1 grade)

Unmeasured
Confounders
Inclusion of
unmeasured
confounders increases the magnitude of effect (+1 grade) High

Moderate

Low

Very Low35 After determining the GRADE of the evidence base for each outcome of a given intervention or question, we calculated the overall GRADE of the evidence base for that intervention or question. The overall GRADE was based on the GRADE category occurring most often for the outcomes deemed critical to making a recommendation; if more than one GRADE category occurred at the same counts, the overall GRADE was based on the lowest GRADE. For questions that had no outcomes that were deemed critical by the working

gro up, no overall GRADE was assigned to the evidence. GRADE definitions are as follows in Table 7 :

Table 7

. Interpretation of GRADE Ratings

Quality Rating Interpretation

High Further research is very unlikely to change our confidence in the

estimate of effect

Moderate Further research is likely to have an important impact on our confidence

in the estimate of effect and may change the estimate

Low Further research is very likely to have an important impact on our

confidence in the estimate of effect and is likely to change the estimate

Very Low Any estimate of effect is very uncertain

Note : These interpretations are from Box 2 of Guyatt et al. (2008). 29



## Formulating Recommendations

Narrative evidence summaries were then drafted by the guideline authors using the evidence and GRADE tables. One summary was written for each key question. The guideline authors used the narrative evidence summaries to develop guideline recommendations. In some instances, multiple recommendations emerged from a single narrative evidence summary.

Factors determining the strength of a recommendation included : 1. the values and preferences we used to determine which outcomes were critical,

2. the harms and benefits that emerged by weighing the critical outcomes, and

3. the overall GRADE of the evidence base for the given intervention or question

. The new categorization sc heme for recommendations is provided in Table 8

. 31

If weighing the critical outcomes for a given intervention or question resulted in a net benefit or a net harm, then a Category I Recommendation was form ulated to recommend strongly for or against the given intervention respectively. If weighing the critical outcomes for a given intervention or question resulted in a tradeoff between benefits and harms, then a Category II Recommendation was formulated to r ecommend that providers or institutions consider the intervention when deemed appropriate. If weighing the critical outcomes for a given intervention or question resulted in an uncertain tradeoff between benefits and harms, then a No
Recommendation was for mulated to reflect this uncertainty.

Category I recommendations are defined as strong recommendations with the following implications:
1. For patients: Most people in the patient‟s situation would want the recommended course of action and only a small propo rtion would not; patient should request discussion if the intervention is not offered.36 2. For clinicians: Most patients should receive the recommended course of action.
3. For policymakers: The recommendation may be adopted as policy or is current federal and/or state statutes, regulation, or standards

.

Category II recommendations are defined as weak recommendations with the following implications:
1. For patients: Most people in the patient‟s situation would want the recommended course of action, but many would not. 2. For clinicians: Different choices will be appropriate for different patients and clinicians must help each patient to arrive at a management decision consistent with her or his values and preferences

. 3. For policymakers: Policy making will require substantial debate and involvement of many stakeholders.

L evels A and B represent the quality of the evidence underlying the recommendation, with A representing high to moderate quality evidence and B representing low to very low

- quality evidence

. Level IC represents required practices, regardless of the quality of evidence.

Expert Opinion. Recommendations from the Expert Opinion are linked to key questions. These recommendations were agreed upon by expert consensus and are designated either IB i f they represent a strong recommendation based on accepted practices or IIB if they are a weak recommendation

.

Previous Guideline and Recommendations. Our evidence

- based recommendations were cross

- checked with those from guidelines identified in our original systematic search. We identified 15 r ecommendations from the
1994 PHS Guidelines for Preventing Transmission of HIV through Transplantation of Human Tissue and Organs 1 for topics not directly addressed by our systematic review of the evidence and included these
recommendations in our Summary of Recommendations as they were deemed critical to the target users of this guideline

. The recommendat ions were revised to make applicable to current expected or actual practice. Three
recommendations

, in response to a 2009 HIV transmission from a living organ donor

, 10 were deemed critical to the target users and included in the Summary of Recommendations for the same reason . Unlike recommendations informed by our literature search, these recommendations are not linked to a key question and were listed as Category I recommendations as the critical outcome for each intervention was determined to
result in a net benefit

.

It is important to note that the strength of a Category IA recommendation is equivalen t to that of a Category IB or IC recommendation; it is only the quality of the evidence underlying the IA recommendation that makes it
different from a IB or IC

. For IB recommendations, although there may be low to very low

- quality evidence directly suppor ting the benefits of the intervention, the theoretical benefits are clear, and the theoretical risks are marginal.

Table 8 . Categorization Scheme for Recommendations

Category IA Strong recommendation supported by high to moderate quality evidence

suggesting net clinical benefits or harms.

Category IB Strong recommendation supported by low to very low quality evidence

suggesting net clinical benefits or harms.

Category IC Strong recommendation required by state or federal regulation , regardless

of quality of evidence

.

Category IIA Weak recommendation supported by high to moderate quality evidence

suggesting a trade

- off between clinical benefits and harms.37 Category IIB Weak recommendation supported by low to very low quality evidence

suggesting a trade

- off between clinical benefits and harms.

No
recommendation Unresolved issue for which there is any quality evidence with uncertain

trade

- offs between clinical benefits and harms.

The wording of each recommendation was carefully selected to reflect the recommendation's strength. We used the active voice when writing Category I recommendations

- the strong recommendations. Phrases like “must”

" should " or " should not" and verbs without conditionals were used to convey certainty. We used a more passive voice when writing Category II recommendations

- the weak recommendations. Words like "consider” and phrases like " may be considered ” or “ should be considered ” were chosen to reflect the lesser certainty of the Category II recommendations. Rather than a simple statement of fact, each recommendation is actionable, describing precisely a proposed action to take. All recommendations focus only on efficacy, effecti veness, and safety. Yet, the optimal use of these guidelines should include a consideration of the costs relevant to the local setting of guideline users.

The category "No recommendation/unresolved issue" was most commonly applied to situations in which e ither 1) the overall quality of the evidence base for a given intervention was low to very low and there was no consensus on the benefit or risks of the intervention or 2) there was no published evidence on outcomes deemed critical to weighing the risks an d benefits of a given intervention. If the latter was the case, those critical outcomes were noted at the end of the relevant evidence summary.



## Tables and Figures in the Evidence Report

The Tables (in italics) and Figures (in italics) in this guideline a re from the evidence report Solid Organ Transplantation and the Probability of Transmitting HIV, HBV, or HCV: A Systematic Review to Support an
Evidence

- based Guideline , except for Table 3. After a period of public comment for the guideline , the evidence

r eport will be posted on the CDC website http://www.cdc.gov/transplantsafety

.



## Finalizing the Guideline

After a draft of the tables, narrative summaries, and recommendations was completed, the guideline authors
shared the draft guideline with the E xpert P anel and R eview C ommittee for an in

- depth review. R evisions to the guideline were made based in part on feedback from members of the E xpert P anel and R eview C ommittee

. The opinions of individual members of the Expert Panel or Review Committee were not fully reflected in this document as the guideline represents the position of the Public Health Service agencies , and is not a consensus
document

. The CDC then submitted the guideline for review and approval by HHS operating divisions. Following further rev isions, the guideline was posted on the Federal Register for public comment. After a period of public comment, the guideline will be revised accordingly, and the final guideline will be published and posted on the CDC website http:// www. cdc.gov/transplant safety

. 

## Updating the Guideline

Future revisions to this guideline will be dictated by new research and technological advancements for preventing transmission of HIV, HBV, and HCV through solid organ transplantation, and will occur at the request of the C DC.38 

## VII . Evidence Review

The t ables listed in the Evidence Review correspond to t ables in the Evidence Report accessible at http:// www.regulations.gov

.

TOPIC I: PROBABILITY OF TRANSMISSION OF HIV, HBV, OR HCV THROUGH SOLID ORGAN
TRANSPLANTATION (Questions 1and 2)



### Question 1. What are the prevalence and incidence rates of HIV, HBV
, and HCV pathogens among potential solid organ donors?

For the three listed pathogens, the quality of evidence for U.S. incidence (the percentage of potential organ donors who newly acquire the pathogen) and prevalence (the percentage of potential organ donors at a given time who test positive for the pathogen) rates were reviewed. Due to th e small amount of evidence on potential solid organ donors, the scope was expanded to include other possibly relevant populations. Ultimately, the search comprised potential deceased and living solid organ donors, 5

, 33

- 44 potential tissue donors, 45 and the U.S. general population. 46

- 51 The U.S. general population studi es did not indicate if cases included living organ or
tissue donors. Testing methods and criteria varied among the included studies. Some studies reported hepatitis prevalence but did not differentiate HBV from HCV. Additionally, it is not clear if antibod y tests were confirmed by a more specific method such as Western blot, recombinant immunoblot assay (RIBA) or NAT in most of these studies. These differences in donor populations and methods used to diagnose and report infection probably contributed to the range in reported incidence and prevalence rates.

Q1.A. HIV Prevalence and Incidence There was low quality evidence from four studies that examined HIV prevalence and incidence among donors and the general population in the United States , and no studies providing data from 2000 or later for potential deceased or living organ donors. ( Table 12 ) Of the four studies that provided “prevalence” data, two related to organ donation.( Table 7

) In a 1995 study of potential living

- related donors, 0% of 22 were HIV p ositive. 34 In a 1993 study of deceased potential organ donors, 2% of 94 were positive for HIV or syphilis; it was unclear if all potential donors had been tested for HIV. 36 Among 10,910 potential tissue donors, the prevalence of confirmed
HIV was 0.093%. 45 ( Table 9 ) HIV prevalence in a U.S. general population study was approximately 0.37%. 52
( Table 11 ) The U.S. general population studies did not indicate if cases included living organ or tissue donors. Our search did not identify studies estimating “incidence” of HIV in organ donors. However, two U.S. studies looked at HIV incidence in the tissue donor and general population. The estimated incidence was 30.11 per 100,000 person

- years among potential tissue donors 45 ( Table 9 ) and 18.8 per 100,000 person

- years among the U.S. general population. 46

, 47 ( Table 11 )

Q1.B. HBV Prevalence and Incidence Review of the available studies found low quality evidence estimating HBV prevalence and incidence in donors and the general population in the United States ( Table 12 ) Five studies provided prevalence data. 34

- 36

, 45

, 50
Among 446 potential organ donors, 4.9% were positive for HBV. 35 The rate of vi ral hepatitis, type unspecified, was 5.3% in a study of 94 deceased potential donors; it was unclear if all potential donors had been tested for

HBV in this study

. 36 A second study of hepatitis, type unspecified, reported a prevalence of 18.2% among potential living

- related organ donors. 34 ( Table 7 ) Among 10,901 potential tissue donors, the prevalence of
confirmed HBV was 0.229%. 45 ( Table 9 ) The prevalence of HBV chronic infection in the U.S. general population, including incarcerated individua ls, was 0.36%. 50 ( Table 11 ) Our search did not identify studies estimating incidence of HBV in organ donors. However, two U.S. studies looked at HBV incidence in tissue39 donor s and the general population. T he incidence of HBV was 18.325 per 100,000 person years for potential
tissue do nors 45 ( Table 9 ) and 14.4 per 100,000 person

- years f or the general population. 48

, 49 ( Table 11 )

Q1.C. HCV Prevalence and Incidence We found low quality evidence from nine U.S. studies that estimated HCV prevalence and incidence in donors and the general population. ( Table 12 ) M ost of the prevalence data for organ donors was derived from d onations that occurred before 1992. Among 55 potential living

- related donors, the prevalence of HCV was 3.6 %. 33 A 1993 study of 94 deceased potential donors identified 5.3% as having active hepatitis, type unspecified; it was

not clear if all 94 potential donors had been tested. 36 Another study reported the prevalence of u nspecified hepatitis at 18.2% among potential living

- related donors. 34 ( Table 7 ) Of four retrospective studies of organ donation that occurred from 1986 to 1992, the combined estimate of HCV prevalence was 4.0%; 37

- 44 three of the studies comprised deceased donors and the fourth did not re port whether donors were deceased or living. ( Table 8 ) The prevalence of HCV was 1.091% among 10,915 potential tissue donors. 45 ( Table 9 ) The prevalence of HCV chronic infection in the U.S. general population, excluding incarcerated individuals, was
1.1%. 51 ( Table 11 ) Our search did not identify studies estimating “incidence” of HCV in organ donors. However, two U.S. studies looked at HCV incidence in tissue donor s and the general population. T he incidence of HCV was 12.380 per 100,000 person

- years for potential tissue donors. 45 ( Table 9 ) and 5.7 per 100,000

person

- years f

or the general population. 48

, 49 ( Table 11 )



### Question 2. What are the rates of transmission to recipients from donors infected with HIV, HBV, or HCV? Do the rates vary by the organ transplanted or when the donor was
infected?

This question concerns the specific situation when the donor tests positive for a pathogen but the transplant
candidate does not. No studies were identified that reported on HIV transmission results likely due to federal regulations that prohibit transplan tation of organs from individuals known to be HIV

- infected . However, a number of studies addressed HBV and HCV, where considerable variation in transmission rates was observed. This variation could have been influenced by numerous factors, including :

● the o rgan transplanted;

● whether HBV prophylaxis was used in the case of an HBV

- positive donor ;

● type of serologic testing used for detection;

● the specific antibodies or antigens for which the donor was positive;

● when the studies were performed

, as earlier ge nerations of HCV serological assays were less sensitive than the current generation;

● whether NAT screening, which would detect recent infection, was performed; and

● the frequency and length of follow

- up testing after transplantation. Figures 4 through 10 p rovide data on some of these factors to aid interpretation of results.

We considered HBV transmission rates where the donor was anti

- HBc positive with HBsAg status unknown to
be the most critical (no studies were found that examined transmission rates fro m anti

- HBc and HBsAg positive donors), except when the recipient tested anti

- HBs positive . For HCV, positive anti

- HCV results may reflect patients who had HCV in the past and cleared the infection. Therefore, we considered transmission rates where
the dono r was positive for HCV ribonucleic acid (RNA) to be most critical . The rows addressing these critical
results for HBV and HCV are shaded in Table 21.

Q2.A. HBV transmission from liver transplantation We found low quality evidence from 17 observational studies 53

- 74 that examined the transmission rate of HBV from infected donors to uninfected recipients. ( Table 21 ) Transmission rates were likely underreported in some40 studies as the use of prophylaxis can result in negative recipient testing despite trans mission. Studies measured virus transmission in 14 different ways with results ranging from 0% to 94% ( Table 14, Figures 4 and 5 ). This difference may be due to whether HBV prophylaxis was used, with the lowest rates found primarily in studies
where all re cipients received prophylaxis

. There was also significant variation in the frequency of post

transplant screening and liver biopsy. 71 Eight st udies reported de novo HBV infection occurring in 72 recipients
between 3 and 48 months post

- transplant

. 54

, 55

, 57

- 63

, 73

, 75 ( Table 23 )

Q2.B. HBV transmission from kidney transplantation This review found low quality evidence from 9 ob servational studies 63

, 65

, 66

, 72

, 75

- 80 regarding estimated
transmission rate s of HBV from infe cted donors to uninfected recipients. ( Table 21 ) Transmission rates were likely underreported in some of the studies as the use of prophylaxis can result in negative recipient testing despite transmission. Studies measured virus transmission in 13 differen t ways for transmission of HBV from kidney transplantation with results ranging from 0% to 13% ( Table 15, Figures 6 and 7 ). Of the f our critical
transmission rates where the donor was anti

- HBc positive with HBsAg status unknown , HBV was not detected.

N one of these four studies reported whether prophylaxis was used. D e novo HBV infection occurred in 0 recipients between 3 and 12 months post

- transplant

. 75 ( Table 23 )

Q2.C. HBV transmission from heart transplantation We found very low quality evidence from 6 observational studies 63

, 65

, 66

, 81

- 85 regarding transmission rate s of

HBV from infected donors to uninfected recipients. ( Table 21 ) Transmission rates are likely underreported in some of the studies as the use of prophylaxis can result in negative recipient testing despite transmission. Studies measured virus transmission in nine different ways for transmission of HBV from heart transplantation with results ranging from 0% to 65% ( Table 16, Figure 7 ). Of the two critical transmission rates where the
donor was anti

- HBc positive with HBsAg status unknown , the range was 18 to 65% when recipients were tested
for anti

- HBc 63

, 82 and 0% to 4% when tested for HBsAg; 63

, 81 none of these studies reported whether prophylaxis
was used. F requency of post

- transplant screening varied in three studies that reported this

. 81

, 83

, 84 Two studies reported de novo HBV infection occurring in 1 recipients between 6

- 10 hours and 10 months po st

transplant. 81

, 82 ( Table 23 )

Q2.D. HBV transmission from lung transplantation
Review of the one s tudy that met inclusion criteria found low quality evidence estimating HBV transmission
from infected donors to uninfected recipients. ( Table 21 ) The study measured virus transmission in two different ways; no recipients were reported as having a positive test ( Table 17 , Figure 7

). 86 A ll recipients
receive d prophylaxis, which may result in negative recipient testing despite transmission. The study did not report on the frequency of post

- transplant screening , and n o de novo HBV post

- transplant infections were reported. ( Table 23 )

Q2.E. HCV transmission fro m liver transplantation We found low quality evidence from two studies 37

, 44

, 87 that looked at transmission rate s of HCV from infected donors to uninfected recipients. ( Table 21 ) Studies measured virus transmission in three different ways for transmission of HCV from liver transplantation with results ranging from 24% to 100%. ( Table 18, Figure 8 )
HCV transmission was detected in 67% of recipients tested for anti

- HCV and 100% of r ecipients tested for
HCV

- RNA in one study where transmission rates were considered critical . The frequency of performing post

transplant immunoassay testing varied considerably

. 37

, 44

, 87 One study reported de novo HCV infection occurring
in 48 recipients withi n 2 4 months

. 37

, 44 ( Table 23 )

Q2.F. HCV transmission from kidney transplantation There was very low quality evidence from 10 studies 5

, 38

- 43

, 88

- 97 that examined transmission rates of HCV from infected donors to uninfected recipients. ( Table 21 ) Studies measured virus transmission in eight different ways41 with results ranging from 0% to 100% ( Table 19, Figure 9 ). Of the four critical transmission rates identified, the range was 0% to 35% when recipients were tested for anti

- HCV, 38

, 95

, 96 0% when tested for RIA, and 0% to 57%
when tested for HCV

- RNA. F our studies reported the fre quency of post

- transplant immunoassay testing which
varied such that the data were not useful

. 5

, 39

- 41

, 91

, 92

, 97 Five studies reported de novo HCV infection occurring in
41 recipients between 10 and 60 months post

- transplant. 42

, 43

, 91

- 93

, 95

- 97 ( Table 23 ) The quality of evidence was rated as very low. ( Table 21 )

Q2.G. HCV transmission fr om heart transplantation
Review of f

our observational studies 98

- 103 found very low quality evidence regarding transmissio n rate s of HCV
from infected donors to uninfected recipients. ( Table 21 ) Studies measured virus transmission in six different ways for transmission of HCV from heart transplantation with results ranging from 11% to 100%. ( Table 20, Figure 10 ) Two critical transmission rates detected HCV transmission in 44% of recipients when tested for anti

HCV and 100% when tested for HCV

- RNA. 56 One study reported regular monitoring without stating a frequency of post

- transplant serology testing. 56 One study reported de novo HCV infection occurring in 3 recipients between 19 and 55 months post

- transplant. 102 ( Table 23 )

Questions 1 and 2 Recommendations

1.A. Further research is needed to estimate the incidence and prevalence of HIV, HBV and HCV

among deceased potential organ donors in the U.S. (No Recommendation/unresolved issue) (Question 1)

1.B. Deceased p otential organ donors should be screened for HCV using NAT or the most sensitive test available regardless of risk of having HCV and regardless of time relative to procurement (i.e., Donor specimens should be obtained before procurement; however, NAT results should be obtained either before, if timing allows, or after procurement)

. (Category IB) (Question 1)42 Figure 4. LIVER Transplantation: HBV Positivity in Recipients after the Use of Anti

- HBc+ Donors

Note : This figure displays the reported rates of positivity among pre

- transplant negative recipients after receiving organs from positive donors. The title of the figure indicates the relevant pathogen(s) and organ(s). The definitions of donor positivity appe ar on the left side of the figure, and the definitions of recipient post

- transplant positivity appear on the right side of the figure.43 Figure

- 5. LIVER Transplantation: HBV Positivity in Recipients after the Use of Organs from
Anti

- HBc+ HBsAg

- Donors

Note : This figure displays the reported rates of positivity among pre

- transplant negative recipients after receiving organs from positive donors. The title of the figure indicates the relevant pathogen(s) and organ(s). The definitions of donor positivity appe ar on the left side of the figure, and the definitions of recipient post

- transplant positivity appear on the right side of the figure.44 Figure 6. KIDNEY Transplantation: HBV Positivity in Recipients after the Use of Organs from Anti
HBc+ Donors or Anti

- H Bc+ HbsAg

- Donors

Note : This figure displays the reported rates of positivity among pre

- transplant negative recipients after receiving organs from positive donors. The title of the figure indicates the relevant pathogen(s) and organ(s). The definition s of donor positivity appear on the left side of the figure, and the definitions of recipient post

- transplant positivity appear on the right side of the figure.45 Figure 7. Kidney, Heart and Liver: HBV Positivity in Recipients after the Use of Organ Donor s Positive
for HBV

Note : This figure displays the reported rates of positivity among pre

- transplant negative recipients after receiving organs from positive donors. The title of the figure indicates the relevant organ(s). The definitions of donor positivity appear on the left side of the figure, and the definitions of recipient post

- transplant positivity appear on the right side of the figure.46 Figure 8. LIVER transplantation: HCV Positivity in Recipients after the Use of Organs Donors Positive
for HCV

Note : This figure displays the reported rates of positivity among pre

- transplant negative recipients after receiving organs from positive donors. The title of the figure indicates the relevant organ(s). The definitions of donor positivity appear on the left side of the figu re, and the definitions of recipient post

- transplant positivity appear on the right side of the figure. Prophylaxis was not generally applicable to the HCV studies, therefore all studies are represented by X‟s.47 Figure 9. KIDNEY Transplantation: HCV Posi tivity in Recipients after the Use of Organs from Donors
Positive f or HCV

Note : This figure displays the reported rates of positivity among pre

- transplant negative recipients after receiving organs from positive donors. The title of the figure indicates the relevant organ(s). The definitions of donor positivity appear on the left s ide of the figure, and the definitions of recipient post

- transplant positivity appear on the right side of the figure.48 Figure 10. HEART Transplantation: HCV Positivity in Recipients after the Use of Organs from Donors
Positive for HCV

Note : This figure displays the reported rates of positivity among pre

- transplant negative recipients after receiving organs from positive donors. The title of the figure indicates the relevant organ(s). The definitions of donor positivity appear on the left side of t he figure, and the definitions of recipient post

- transplant positivity appear on the right side of the figure. Prophylaxis was not generally applicable to the HCV studies, therefore all studies are represented by X‟s.49 TOPIC II: METHODOLOGY TO BETTER ESTI M ATE DONOR INFECTION WITH HIV, HBV, OR
HCV (Questions 3, 4, 5)



### Question 3 . What behavioral risk factors are associated with an increased probability of infection with HIV, HBV
, or HCV? What is the prevalence of these characteristics among potential solid organ donors?

T he first half of the question attempts to identify behaviors that may put individuals at increased risk for HIV,
HBV

, or HCV , while t he second half of the question addresses the frequency of those behaviors among potential solid organ dono rs. The following sections present all behaviors identified as exclusion criteria from the 1994 guideline, as well as additional behaviors identified from the literature but not i ncluded as exclusion
criteria from the 1994 guideline. The prior guideline stated that “Regardless of their HIV antibody test results, persons who meet any of the criteria liste d should be excluded from donation of organs or tissues unless the risk to the recipient of not performing the transplant is deemed to be greater than the risk of HIV transmission and
disease

. ” :

● Men who have sex with men in the preceding 5 years;

● persons who report nonmedical intravenous, intramuscular, or subcutaneous injections of drugs in the preceding 5 years;

● persons with hemophilia or related clotting disorders who have received human

- derived clotting factor

concentrates;

● men and women who have engaged in sex in exchange for money or drugs in the preceding 5 years;

● persons who have had sex in the preceding 12 months with any person described in the abo ve items or with a person known or suspected to have HIV infection;

● persons who have been exposed in the preceding 12 months to known or suspected HIV

- infected blood through percutaneous inoculation or through contact with an open wound, nonintact skin, or mucous membrane;

● inmates of correctional systems;

● children meeting any of the exclusionary criteria listed above for adults;

● children born to mothers with HIV infection or mothers who meet the behavioral exclusionary for adult
donors unless child> 18 mont hs of age, who is born to mother with or at risk for HIV infection, has not been breast fed with the last 12 months, and HIV antibody tests, physical examination and review of medical records do not indicate evidence of HIV infection; and

● child≤ 18 months of age, who is born to a mother with or at risk for HIV infections or has been breast fed within the past 12 months

Given the paucity of data evaluating behavioral risk factors for HIV, HBV and HCV in potential organ donors, we also searched for studies meeting inclusion criteria in the following populations: general population (i.e., unselected for any particular demog raphic, occupational, or behavioral characteristics, or health status other than HCV, HBV, or HIV infection ), tissue donors, and blood donors . After broadening the search, there were only a few articles meeting inclusion criteria that identified behavioral risk for HBV. Therefore, studies of demographic or socioeconomic subpopulations, such as college students or veterans admitted to a psychiatric inpatient ward were included for HBV

. In addition, there was a lack of data for evaluating nonbehavioral risk
f actors in organ donors.

Based on the quality of evidence from the literature review, the association of behavioral and nonbehavioral factors with the risk of HIV, HBV or HCV was categorized as follows. Behavioral and nonbehavioral
characteristics that wer e associated with HIV, HBV, or HCV and identified by “low

, ” “moderate

, ” or “high” quality evidence in the systematic revi ew are reported in Table 9 of this document . Due to the lack of evidence50 in the literature meeting inclusion criteria identifying risk factors for incident infection, the potential risk factors
identified from the literature review in Table 9 were modified by subject matter experts on HIV and hepatitis to create a revised list of risk factors for screening in Table 3 of this document . The revised list takes into consideration that 1) certain risk factors can be omitted because they are likely markers for other factors identified in the systematic review and 2) certain risk factors should be added because scientific evidence associating cer tain factors with the bloodborne pathogens exists, but may not have met the inclusion criteria of the system atic review or studies were of insufficient quality to draw conclusions.

Q 3 .A. HIV and Behavioral Risk Factors

Exclusionary Criteria from the 199 4 Guideline

Q 3 .A.1 Men Who Have Sex with Men (MSM)
There was moderate quality evidence identifying MSM as a risk factor for HIV. ( Table 36 ) The 1994 guideline excludes from becoming organ donors “Men who have had sex with another man in the preceding 5 years.” We identified zero studies that addressed this particular time frame. Two studies of the general population, one using National Health and Nutrition Examination Survey ( NHANES) data 104 and the other using New York City HANES data

, 105 found a significantly higher rate of HIV for MSM in univariate analyses

. 105 Among infected males, 52% 104 and 53.8% 105 reported a history of MSM behavior. ( Table 35 ) The prevalence of MSM

, reported as 3.7% 104 and 9.3% 105 of men in the general population studies, was rated as low quality evidence

. ( Table 37 )

Q 3 .A.2. Injection Drug Use (IDU) We found low quali ty evidence suggesting an association between IDU and HIV. ( Table 36 ) The 1994 guideline excludes from becoming organ donors “Persons who report nonmedical intravenous, intramuscular, or subcutaneous injection of drugs in the preceding 5 years.” We identif ied zero studies that investigated the risk of IDU within this particular time frame; most studies evaluated lifetime IDU. S tudies typically did not distinguish between IDU and intravenous drug use (IVDU). Two studies of the general population, using
NHANE S and HANES data, found significant association s between IDU and HIV with large effect sizes in univariate analyses. 104

, 105 ( Table 35 ) A third study of patients at an urban medical care center did not find an
associat ion in univariate analysis. 106 The prevalence of IDU

, reported as 1.4% 105 and 7.9%

, 106 ( Table 37 ) was rated as low quality evidence. ( Table 38 )

Q3.A.3. Sex Worker A single study found very low quality evidence which did not find an association between sex workers and HIV. ( Table 36

) The 1994 guideline excludes from becoming organ donors “Men and women who have engaged in sex in exchange for money or drugs in the preceding 5 years.” We did not find any literatur e that studied the association between this factor and HIV within this particular time frame. One corneal donor study involving a next

- of

- kin interview did not find any association between sex work and infection with HIV. 107
( Table 35 ) One urban medical care center reported a 2.3% prevalence of exchanging sex for drugs or money, 106
( Table 37 ) and this evidence was rated low quality. ( Table 38 )

Q 3 .A.4. High Risk Sex Partner The 1994 guideline excludes from becoming organ donors persons who have had sex in the preceding 12 months with any of the following persons: MSM, IDUs, sex workers, or persons known or suspected to have HIV infection. We did not identify any literature on infection risk in people with high

- risk sex partners during
the listed time frame.51 Q 3 .A.4. a

. Sex with Injection Drug User Our search did not identify studies that examine the association between sex with an injection drug user and acquiring HIV.

Q 3 .A.4. b

. Sex with a Sex Worker
No studies were identified that looked at the association between HIV and sex with a sex worker. O ne study in
an urban medical care center reported 7.4% of patients had had sex with a sex worker 106 ( Table 37 ) an d this evidence was rated low quality ( Table 38 ).

Q 3 .A.4. c

. Sex with People Known to be HIV Infected There was low quality evidence associating having sex with someone who is HIV

- positive and having HIV. (Table 36) One study of a general population found that the relationship between having a sex partner with HIV
and acquiring HIV was significant with a large magnitude of effect in a univariate analysis. 106 ( Table 35 ) The study reported that 3.6% of participants indicated having sex with someone known to be infected with HIV. 106
( Table 37 ) , and this evidence was rated low quality. ( Table 38 )

Q 3 .A.4. d

. Other High Risk Sex Partners
No studies were identified that met the inclusion criteria.

Q 3 .A.5. Inmates A single study found very low quality evidence to suggest an association between being incarcerated and having HIV. ( Table 36 ) The 1994 guideline excludes from becoming organ donors inmates of correctional systems. No
studies that examined the association between “ present ” incarceration and in fection were identified. However, one study examined and did not identify an association of lifetime history of incarceration as reported by next

of

- kin with HIV infection in potential corneal donors. 107 ( Table 35 )

Q 3 .A.6. Risk Factors in Children We identified no literature on any behavioral risk factors in children, or on the risk of infection from mothers who engage in those risk behaviors. While vertical transmis sion is generally recognized as a mode of hepatitis or HIV transmission, this body of literature lacks the evidence to assess the 1994 criteria as risk factors.

Additional Potential Behavioral Factors for HIV from 2009 Literature Search

Q 3 .A.7. Multiple Sex Partners Review of the available studies reveals low quality evidence to suggest an association between having multiple sex partners and being at increased risk of HIV. ( Table 36 ) Studies defined multiple partners using different
thresholds. Having multiple partners, including heterosexual partners, was associated with HIV infection in one general population study of hospital inpatients and outpatients

. 104 HANES data of New York City adult s found having multiple sex partners in the past ye ar was not associated with HIV, 105 nor was having at least 10 lifetime sex partners in the patient study, 106 but having 50 or more lifetime sex partners was associated with HIV in an NHANES study. 104 All of these analyses were univariate. ( Table 35 ) In the studies, 3.5% 104 and 6.6% 105 reported having at least 50 lifetime sex partners; 74% reported having sex with at least two partners 104 and with
2

- 49 partners during their lifetime; 105 whereas 22% reported having sex with multiple partners during the

pr evious year. 105 ( Table 37 ) We found low quality evidence regarding the prevalence of individuals having at least 50 partners, whereas we found moderate quality evidence regarding prevalence estimates of having multiple sex partners, at least 2 sex partners, and between 2 and 49 partners. ( Table 38 )5 2 Q3.A.8. Same Sex Partners We found low quality evidence to suggest an association between having a same sex partner and acquiring HIV. ( Table 36 ) A univariate association with a large magnitude of effect between having a same

- sex partner and HIV, including both men and women was detected in a general population study

. 106 ( Table 35 ) The prevalence
of same

- sex partners was reported as 8.2% 106 ( Table 36 ) , and this evide nce was rated low quality. ( Table 38 )

Q3.A.9. Age at First Sexual Intercourse There was low quality evidence to support younger age at first sexual intercourse as a risk factor for HIV infection. ( Table 36 ) An NHANES study reported that first sexual inter course at 18 years or younger was
associated with HIV in univariate analysis with a large effect size

. 104 ( Table 35 ) The proportion of adults who reported having sex at age 18 or younger was 59%

, 104 ( Table 37 ) and this evidence was rated high quality. ( Table 38 )

Q3.A.10. Additional Various [Sexual] Associations We report additional reported associations between sexual practices and infection identified in the literature but did not assign GRADE ratings because these factors were reported by so few studies. Not using condoms was not associated with HIV infection in two general population studies. 105

, 106 Anal

- insertive sex that occurred at least six weeks ago, and anal

- receptive sex at least six weeks ago among women and men was associated with HIV in a general populat ion. 106 Having vaginal sex was associated with a reduced risk in HIV compared with people who did not have vaginal sex (bu t may have been having anal sex) in the general population study. 109
( Table 35 )

Q3.A.11. Non

- injection Substance

Q3.A.11.a. Other Illicit Drugs We found low quality evidence associating use of cocaine or street drugs and HIV infection. ( Table 36 ) HIV was associated with any prior cocaine or street drug use in univariate analysis using NHANES data 104 and in multivariate analysis 108 among members of the general population. ( Table 35 ) The proportion of respondents who reported using street drugs/cocaine was 21%

, 104 ( Table 37 ) and this evidence was rated moderate quality due to indirectness. ( Table 38 )

Q3.A.11.b. Alcohol There was very low quality evidence associating alcohol with an increased risk of HIV. ( Table 36 ) HIV was associated with having an alcohol and/or (unspecified) drug problem among health maintenance organization s ( HMO ) enrollees, 109 but not with alcohol use among potential corneal donors. 107 Both of these analyses were univariate. ( Table 35 )

Q3.A.11.c. Tobacco One study found was very low quality evidence which did not find an association between cigarette use and HIV ( Table 36 ) among corneal donors. 107 ( Table 35 )

Q3.A.12. Tattoos and Piercing One study found very low quality evidence which did not find an association between tattoos, piercings, and acupuncture ( as collectively analyzed as one outcome and reported by next

- of

- kin) in potential corneal donors

. ( Table 36 )

. 107 ( Table 35 )

Q3.A.13. International Travel One study r evealed very low quality evidence that did not find an association between international travel and HIV ( Table 36 ) a mong potential corneal donors. 107 ( Table 35 )53 Q3.B. HBV and Behavioral Risk Factors

Exclusionary Criteria from the 1994 Guideline

Q 3 .B.1. Men Who Have Sex with Men (MSM) The review demonstrated moderate quality evidence to support an association between MSM behavior and

HBV. ( Table 36 ) The 1994 guideline excludes from becoming an organ donor “Men who have had sex with another man in the preceding 5 years.” We identified zero studies that address ed this particular time frame. Two studies found associations with HBV. One study compared the prevalen ce of HBV among MSM in a sample drawn from the general population (4.7% HBV positive) to those who self

- report as not MSM (age

- adjusted prevalence of HBV 5.7%) and found a significantly increased prevalence of HBV (age adjusted prevalence 26.8%) among MSM. 110 In a population of college students, H BV infectio n rates among MSM were compared
to men who have never had sex and showed that the rate of HBV was higher among MSM in both univariate and multivariate analyses. 111 For both studies, the magnitude of the effect was large. ( Table 33 )

Q 3 .B.2. Injection Drug Use (IDU) There was low quality evidence to support IDU as a risk factor for HBV infection. Although all but one study found an association, not all of the studies found a large magnitude of effect. ( Table 36 ) The 1994 guideline excludes from becoming an organ donor “Persons who report nonmedical intravenous, intramuscular, or subcutaneous injection of drugs in the preceding 5 years.” We identified zero studies that investigated the risk
of IDU within the listed time frame; most studies associated lifetime IDU with infection. In general, studies did not distinguish between IDU and intravenous drug use IVDU. HBV was significantly associated with IDU in
four studies

, 111

- 114 and t hree of these studies had large effect sizes, 111

- 113 with a point estimate OR of 2.0 or higher. One study comprised volunteers from the general population

, 112 two comprised IVDU veterans in inpatient psychiatric hospitals, 113

, 114 and one involved college students. 111 Only two stud ies 112

, 114 performed multivariate analyses. The fifth study did not find an elevated risk in an obstetric population. 115 O n e study also considered steroid injection but did not find a significant relationship between injection steroid use and HBV
infection. 111 ( Table 33) Prevalence of injection drug use reported in the general population study was 3.5%. 112
( Table 37 ) , and this evidence was rated low quality. ( Table 38 )

Q3.B.3. Sex Worker We found very low quality evidence relating sex work and HBV infection. ( Table 36 ) The 1994 guideline excludes from becoming an organ donor “Men and women who have engaged in sex in exchange for money or drugs in the preceding 5 years.” We did not find any literature that studied the association between this fa ctor and the given time frame. None of the three studies found an association between sex work (including sex bartering or sex for drugs) and HBV. 107

, 113

, 114 A study of corneal donors did not find any association between sex work and infection with HBV in univariate analysis. 107 Two studies of psychiatric inpatient veterans did not detect an association between sex bartering 113 or unprotected sex for drugs 114 with HBV infection in multivariate analyses. ( Table 33 )

Q3.B.4. High Risk Sex Partner The 1994 guideline excluded persons who have had sex in the preceding 12 months with any o f the following persons from becoming an organ donor: MSM, injection drug users , sex workers, or persons known or suspected to have HBV infection. We did not identify any literature on infection risk in people with high

- risk sex partners during the listed time frame. However, having a high

- risk or infected sex partner was associated
with HBV in six of seven studies.54 Q3.B.4.a. Sex with Injection Drug User Review of the available studies revealed very low quality evidence supporting an association between HBV infection and having sex with an injection drug user. ( Table 36 ) Four studies examined sex with an injection drug user

. 111

- 113

, 116 Sex with an injection drug user was significantly associated with HBV in the general population in multivariate analysis 112 and in univariate analyses among college students 111 but not among veterans admitted to the inpatient psychiatric ward. 113 Sex or household contact with an injection drug user was associated with HBV infection in univariate but not multivariate analysis. 116 ( Table 33 ) In one study, 5% of the general population parti cipants reported having sex with an injection drug user 112 ( Table 37 ), and this evidence was rated low quality. ( Table 38 )

Q3.B.4.b. Sex with a Sex Worker A single study of psychiatric inpatient veterans found very low quality evidence which did not find an association between HBV and having sex with a sex worker ( Table 36 ) in univariate analysis. 113 ( Table 33 )

Q3.B.4.c. Sex with People Known to be HBV Infected There was very low quality evidence to support having a sex partner with a known HBV infection as a risk factor for HBV. ( Table 36 ) Sex with a partner with hepatitis was found to be a significant risk factor for HBV in
coll ege students 111 but not in an obstetric population. 115 Both of these analyses were univariate. ( Table 33 )

Q3.B.4.d. Other High Risk Sex Partners Additional high

- risk sex partners not mentioned in the original guideline were reported by one study. 116 HBV infection was not associated with sex with a blood transfusion recipie nt, with a health care worker, or a person with a foreign birth in an endemic area. This study was reported because it is germane to the larger issue of having high

- risk sex partners. However, the quality of the evidence was not rated because this factor w as reported by one study only. ( Table 33 )

Q3.B.5. Inmates We found very low quality evidence to suggest an association between being incarcerated and having HBV. ( Table 36 ) The 1994 guideline excludes inmates of correctional systems from donating organs. There were no studies identified that examined the association between present incarceration and HBV. However, the search did identify studies that examined the association between recent or lifetime history of incarceration. A history
of incarceration wa s associated with HBV in three of four studies. 107

, 111

, 113

, 116 In the general population, imprisonment within the last six months was associated with recent HBV infection in univariate but not multivariate analysis. 116 Incarceration was also significantly associated with HBV in univariate analysis among psychiatric inpatient veterans 113 and among college students incarcerated for at least 24 hours. 111 A history of incarceration as reported by next

- of

- kin was not associated with HBV in potential corneal donors. 107 ( Table 33 )

Q 3 .B.6. Risk Factors in Children We identified no literature on any behavioral risk factors in children, or on the risk of infection from mothers who engage in those risk behaviors. While vertical transmission is generally recognized as a mode of hepatitis or HIV transmission, this body of literature lacks the evidence to assess the 1994 criteria as risk factors.

Additional Potential Risk Factors for HBV from 2009 Literature Search

Q3.B.7. Multiple Sex Partners Review of the outlined studies demonstrated moderate quality evidence to support having multiple sex partners as risk factor for HBV infection. The strength of this association was due to a positive dose res ponse association. ( Table 36 ) Having multiple partners, including heterosexual partners, was associated with increased
risk of HBV infection in five studies. 110

- 112

, 114

, 116 Studies defined multiple partners using different thresholds. In55 multivariate analyses, HBV infection was associated with sex with multiple partners in a general population 112 and among psychiatric inpatient veterans, 114 and with multiple p artners within the last six months in a general population. 116 In a sample of people representative of the general population, having ≥2

- 9, ≥10

- 14 or ≥50 lifetime sex partners, compared to 0

- 1 lifetime partners, was associated with HBV in multivariate analysis. However, the prevalence of HBV in the general population was 4.7% compared to age

- adjusted prevalence of 4.4% of individuals having 2

- 9 lifetime sexual partners. 110 Among college students, > 50 lifetime heterosexual partners and > 5 heterosexual partners in the preceding four months were both associated with HBV infection in univariate analyses. 111 (Table 33) In one study, 26% of respondents reported having sex with multiple
partners, 112 ( Table 37

) and this evidence was rated moderate quality. ( Table 38 )

Q3.B.8. Same Sex Partners Our search did not identify any studies that examined an association between same sex partners and HBV
infection.

Q3.B.9. Age at First Sexual Intercourse There was low quality evidence to suggest an association between age at first sexual intercourse and HBV infection. ( Table 36 ) Age of 18 years or younger was not associated with HBV in a multivariate analysis of general population participants in an NHANES study. 110 Age at first intercourse of 15 years or younger was
associated wi th HBV infection among college students. 111 ( Table 33 )

Q3.B.10. Addit ional Various [Sexual] Associations Our search did not find other studies regarding association between other sexual behaviors and an increased risk
for HBV.

Q 3 .B.11. Non

- injection Substance

Q 3 .B.11.a. Other Illicit Drugs There was very low quality evide nce associating non

- injection illicit drug use with HBV. ( Table 36 ) Two of
five studies found an association with HBV and non

- injection illicit drugs. 107

, 110

, 111

, 113

, 114 A n NHANES study of the general population found a ny prior cocaine use was associated with HBV in a multivariate analysis , but this study did not control for i njection drug use, a major confounding variable. 110 HBV infection was associated with intranasal drug use among the college students. 124 However, HBV infection was not associated with inhaled or „snorted‟ drugs in psychiatric inpatient veterans. 113

, 114 Illicit drug use was not associated with HBV in

a corneal donor study. 107 ( Table 33 )

Q 3 .B.11.b. Alcohol There was very low quality evidence to suggest an association between alcohol use and HBV infection . ( Table 36) Alcohol use, as reported by next

- of

- kin, was not associated with HBV in fection among potential corneal donors in univariate analysis. 107 HBV was not associated with alcohol use disorder among psychiatric inpatient
veterans in multivariat e analysis. 114 ( Table 33 )

Q 3 .B.11.c. Tobacco A single study found very low quality evidence to suggest an association between tobacco use and HBV. ( Table
36 ) No association was found between cigarette smoking and HBV among corneal donors. 107

Q 3 .B.12. Tattoos and Piercing We found low quality evidence that did not support having tattoos and piercings as a risk factor for HBV. ( Table 36 ) Tattoos, piercing, and acupuncture (collectively analyzed as one outcome and reported by next

- of

kin) were not associated with HBV in corneal donors. 107 Tattoos were not associated with HBV infection56 among psychiatric inpatient veterans, 113 women receiving prenatal care, 115 or among college students, 111 unless the college students were tattooed with reused non

- autoclaved needles. Having a tattoo in the last six months
was not associated with acute HBV infection. 116 Piercings were not associated with HBV among psychiatric inpatient veterans, 113 and body piercings were not associated with HBV among college students. 111 Piercings within the last six months were not associated with acute HBV in the general population ei ther. 116 ( Table 33 )

Q 3 .B.13. International Travel
We found ver y low quality evidence which did not find an association between international travel and having HBV ( Table 36 ) a mong potential corneal donors. 107 ( Table 33 )

Q 3 .C. HCV and Behavioral Risk Factors

Exclusionary Criteria from the 1994 Guideline

Q 3 .C.1. Men Who Have Sex with Men (MSM) There was very low quality evidence to support MSM behavior as a risk factor for HCV infection. ( Table 36 ) The 1994 guideline excludes f rom becoming an organ donor “Men who have had sex with another man in the preceding 5 years.” We identified zero studies that addressed this particular time frame. One study comprising blood donors found a significant association between HCV and MSM in uni variate analysis; however, an increased prevalence was not found adjusting for confounding by IVDU. 117 A general population study found
no association in univariate a nalysis. 118 ( Table 68 )

Q 3 .C.2. Injection Drug Use (IDU) This review demonstrated moderate quality evidence to support IDU as a risk factor for HCV. There were consistently large effect sizes found in all studies except one study on steroid use. ( Table 36 ) The 1994 guideline excludes from becoming an organ donor “Persons who report nonmedical intravenous, intramuscular, or subcutaneous injection of drugs in the preceding 5 years.” We identified zero studies that investigated the
risk of IDU within this time frame; most studies associated lifetime IDU with infection. In general, studies did not distinguish between IDU and IVDU. Three blood donor studies 117

, 119

, 120 and four general population
studies 51

, 109

, 112

, 118 detected associations between IDU and HCV. ( Table 68 ) O ne blood donor stud y found use
within the last six months was associated with infection. 119 One blood donor stud y also considered past steroid injection reported by three donors and did not find an increased risk; however, a trend was found toward higher infection rate longer than six months ago. 119 Two blood donor studies and three general population
studies 51

, 112

, 118 performed multivariate analyses and determined IDU was an independent risk factor; the other studies performed univariate a ssessments only. Additionally, reporting living with an injection drug user was associated with HCV among blood donors, even when adjusted for confounding by IDU, 117 as was living with

an injection drug user in the last six months. 119 A general population study reported that both being a t a social gathering with injection drugs and witnessing the use of injection drugs were associated with HCV. 121 Prevalence of injection drug use reported in the general pop ulation studies were 1.7% 51 and 3.5%. 112 ( Table 37 )

, and this evidence was rated low quality. The lower estimate was derived from NHANES 51 data and the higher was drawn from patients and volunteers in urban areas. 112

Q 3 .C.3. Sex Worker We found low quality evidence to suggest an association between sex work and HCV. ( Table 36 ) The 1994 guideline excludes from becoming an organ donor “Men and women who have engaged in sex in exchange for money or drugs in the preceding 5 years.” We did not find any literature that studied the association betwe en this factor and the given time frame. Sex work was significantly associated with HCV in multivariate

- analysis
in a blood donor study 117 and in univariate analys e s in two general population studies. 118

, 121 However, in one study, all women who reported sex work also reported IDU. 118 One study of corneal donors did not find any57 association between sex work and infection with HCV. 107 ( Table 68 ) One urban medical care center study reported 2.3% of participants reported exchanging sex for money or drugs

, 106 ( Table 37 ) and this evidenc e was rated low quality . ( Table 38 )

Q 3 .C.4. High Risk Sex Partner The 1994 guideline excludes from donating organs persons who have had sex in the preceding 12 months with any of the following persons: MSM, IDUs, sex workers, or persons known or suspected to have H C V infection. We did not identify any literature on infection risk in people with high

- risk sex partners during the listed time frame. Having a high

- risk or infected sex partner was associated with HCV in ten studies.

Q 3 .C.4.a. Sex with Injectio n Drug User Review of the outlined studies found moderate quality evidence supporting having sex with an IDU as a risk
factor for HCV. Studies consistent ly found an association with large magnitude of effect. ( Table 36 ) Sex with

an injection drug user or i ntravenous drug user was significant l y associated with HCV in blood donors in
univariate 117 and multivariate analys e s, 119 and in the general population in univariate 121 and multivariate analysis. 112 ( Table 68 ) In one study, 5% of patients reported having sex with an injection drug user

, 112 ( Table
37 ) and this evidence was rated low quality . ( Table 38 )

Q 3 .C.4.b. Sex with a Sex Worker We found very low quality evidence to suggest an association between having sex with a sex worker and having HCV. ( Table 36 ) Sex with a sex worker was associated with HCV among blood donors in univariate and multivariate analys e s 117 in general population studies; 118

, 121 however, the relationship was no longe r significant in a multivariate analysis. 118 ( Table 68 )

Q3.C.4.c. Sex with People Known be HCV Infected We found low quality evidence to support having sex with people known to be HCV infected as a risk factor for HCV infection in ( Table 36 ) t wo studies of blood donors, one with multivariate analysis 117 and one with univariate analysis 119 One study limited the behavior to the previous six months. 119 ( Table 6 8 )

Q 3 .C.4.d. Other High Risk Sex Partners Some miscellaneous types of high

- risk sex partners pertinent to high

- risk sex partners not mentioned in the original guideline were also reported, such as sexual promiscuity (defined as history of a sexually trans mitted disease ( STD ) or at least five sex partners per year) 120 and sex with a transfusion recipient 117 in blood donors.

We report these studies here because they are germane to the larger issue of having high

- risk sex partners. However, no GRADE rating was given because these two studies reported on different factors. ( Table 68 )

Q 3 .C.5. Inmates We found low quality evidence to support incarceration as a risk factor for HCV. The 1994 guideline excludes from becoming organ donors inmates of correctional systems. No studies that examined the association between present incarceration and infection we re identified. However, the searches did identify studies that examined the association between recent or lifetime history of incarceration. A history of incarceration was associated with
HCV in four of five studies. 107

, 117

, 119

- 121 Incarceration was associated with HCV in three blood donor
studies. 117

, 119

, 120 One study found that incarceration for more than three days was an independent risk factor, 117 while another study found no association once adjusted for confounding by IDU. 120 In addition, having been arrested was associated with HCV infection in a univariate analysis of a general population sample. 121 A history of incarceration as reported by next

- of

- kin was not associated with HCV infection in potential corneal
donors. 107 ( Table 68 )58 Q 3 .C.6. Risk Facto rs in Children We identified no literature on any behavioral risk factors in children, or on the risk of infection from mothers who engage in those risk behaviors. While vertical transmission is generally recognized as a mode of hepatitis
or HIV transmissi on, this body of literature lacks the evidence to assess the 1994 criteria as risk factors.

Additional Potential Risk Factors for HCV from 2009 Literature Search

Q3.C.7. Multiple Sex Partners Review of the outlined studies found moderate quality evidence confirming an association between HCV infection and having multiple sex partners. Studies demonstrated a positive dose

- response association. ( Table
36 ) Having multiple partners (defined using different thresholds) was associated with increased risk of inf ection
in six studies. 51

, 109

, 112

, 117

, 119

, 121 Having at least 11 male sex ual partners (compared to having zero sexual partners) was associated with HCV infection in multivariable analysis in female blood donors, 117 whereas having the same number of lifetime female partners was not associated with HCV in men. Having two or more sexual partners, whether same sex or not, in the last six months was associated with an increased rate of HCV infection overall in a univariate analysis. 119 A general population study did not find HCV was associated with having frequent sex partners 109 multiple sex partners 112 and at least 20 sexual partners in univariate anlaysis. 51 Another general population study also reported greater numbers of sex partners associated with HCV infection in univariate analysis. 121 One study noted the strong association between greater numbers of sex partners and IDU. Of the 18.5% of their patients who reported having at least 10 sex partners in their sample, 84% also reported IDU. 118 ( Table 68 ) In a study of the U.S. general population, 29% of survey respondents indicated
hav ing had at least 10 sex partners 51 and 26% of volunteers from an urban area reported sex with multiple
partners. 112 ( Table 37

) There was moderate quality evidence regarding the prevalence of having multiple sex partners (number undefined) and having at least 2 sex partners. ( Table 38 )

Q3.C.8. Same Sex Partners There was very low quality evidence to suggest an association between same sex partners and HCV. ( Table 36 ) A study of female blood donors found an increased risk of HCV in females with same

- sex partners in multivariate analysis. 117 This risk was no longer significant when adjusted for confounding by IDU. Among outpatients, no association was found between having sex with a person of the same sex and HCV infection in univariate analysis. 121 ( Table 68 )

Q 3 .C.9. Age at First Sexual Intercourse We found low quality evidence associating younger age at first intercourse with HCV infection. This single study identified a dose

- depen dent relationship. ( Table 36 ) In the general population, first sexual intercourse at age of 17 years or younger was associated with HCV in a univariate analysis. The study stratified age at first
intercourse (i.e., age younger than 11, age 12

- 15, and age 1 6

- 17 years ) . The groups of people who were younger at the time of their first sexual intercourse had the highest risk of HCV. 51 ( Table 68 ) The proportion of adults who reported having sex at age 18 or younger was 58% 51 ( Table 37 ) and this evidence was rated moderate quality ( Table 38 )

Additional Various [Sexual] Associations Unprotected sex was associated with HCV infection in a general population. 109 However, we did not assign a GRADE rating because only one study reported this factor. ( Table 68 )59 Q3.C.10. Non

- injection Substance

Q3.C .10.a. Other Illicit Drugs There was low quality evidence associating HCV with non

- injection drug use. ( Table 36 ) Seven of eight studies
found an association with HCV and non

- injection substances. 51

, 107

, 109

, 117

- 121 Intranasal drugs were associated with HCV infection in blood donors, 117

, 119

, 120 when adjusted for confounding by IDU or other factors in two
studies. 117

, 120 In a general population study, use of snorting or inhaling nonprescription drugs, 121 inhaling cocaine, 109 using intranasal cocaine, 118 and use of non

- injection drugs other than marijuana 51 were all associated with increased prevalence of H CV. One of the studies using NHANES data found only a marginal independent
associat ion with HCV between non

- injection drug use (except marijuana) compared to those who reported either no illicit drug or marijuana use

, 51 while another study did not ; however, cocaine use in the absence of IDU or tattoos was unusual in their sample. 118 Being at a social gathering w ith cocaine was associated with
HCV. 121 And having friends who use street drugs was associated with an increased risk of HCV among blood
donors. 119 Illicit drug use was not associated with HCV in a corneal donor study. 107 ( Table 68 ) In the general population, 17% reported lifetime use of drugs other than marijuana 51 ( Table 37 ) , and this evidence was rated moderate quality. ( Table 38 )

Q 3 .C.10.b. Alcohol There was very low quality evidence to suggest a relationship between alcohol use and HCV. ( Table 36 ) HCV was associated with heavy alcohol use in heart donors, 122 and with having at least two units of alcohol per day among adults tested for HCV because of clinical suspici on. 118 However, HCV was not associated with alcohol

use among corneal donors, 107 having at least 5 alcoholic drinks weekly in patients, 121 or alcoholism in HMO
enrollees. 109 All of these analyses were univariate. ( Table 68 )

Q 3 .C.10.c. Tobacco We found very low quality evidence associating tobacco use with HCV. ( Table 36 ) We also found low quality
evidence estimat ing the prevalence of tobacco use

. ( Table 38 ) A history of tobacco use was associated with HCV in heart donors, 122 and cigarette smoking was associated with HCV in corneal donors 107 in univariate analyses. ( Table 68 ) Among actual heart donors, 36% had a history of tobacco use 122 ( Table 37 ) and the evidence was rated low quality

. ( Table 38 )

Q 3 .C.11. Tattoos and Piercing Review of available studies found low quality evidence to associate t attoos and piercings with HCV. Tattoos were consistently associated with HCV in six of seven studies, 107

, 109

, 117

- 121 whereas piercings were inconsistently associated with HCV ( Table 36 ) in three of six studies. 109

, 117

- 121 Three bl ood donor studies reported t attoos were associated with HCV in univariate analys e s. 117

, 119

, 120 One study focused on having had a
tattoo within the last six months and the risk of acute HCV. 119 When multivariate a nalyses were performed, tattoos were not significantly associated with infection in one study

, 119 but remained an independ ent predictor in a second study , although the odds of infection were reduced once adjusted for confounding by IDU. 117 Three general population studies 109

, 118

, 121 also detected significant associations between tattoos and HCV. Only study of the three general population studies foun d that tattoos were an independent predictor. 118 Adults were enrolled based upon clinical suspicion of hepatitis, and most reported that their tattoos had been applied by friends, fellow gang members, or fellow inmates. A mong blood donors, HCV was not associat ed with body piercing in the last 6 months, 119 but was associated with ear piercing among men, 120 and pierced ears or body parts. 117 Two general population studies did not find an association between body piercing and HCV. 109

, 118 In two general population studies, 118

, 121 only one found ear piercing in adult patients was associated with HCV in a univariate analysis. 121 T attoos, piercing, and acupuncture (as collectively analyzed as one outcome and reported by next

of

- kin) were not associated with HCV in potential corneal donors. 107 ( Table 68 )60 Q 3 .C.12. International Travel We found low quality evidence that did not suggest an association between international travel and HCV
infection. Among potential corneal donors, international travel was not associated with HCV. 107 International
travel within the last six months was not associated with acute HCV in a general population 117 or a mong blood
donors . H aving ever lived outside the United States was n ot found to be significantly associated with HCV in a blood donor study

. 117 ( Table 68 )



### Question 4 . What nonbehavioral factors are associated with an increased probability of infection with HIV, HBV
, or HCV? What is the prevalence of these factors among potential solid organ donors?

The primary intent of this question was to identify signs and symptoms of incident infections (i.e., recently acquired), but also i nclude data on signs and symptoms of chronic infection, medical co

- morbidities, socioeconomic information, and demographic factors. The second half of the question addresses the frequency of these nonbehavioral factors. Information regarding exclusionary f actors listed in the 1994 guideline is presented first, and then information regarding additional factors for which at least two studies provided evidence regarding the same factor is presented.

Due to the lack of evidence in the literature meeting inclusion criteria identifying risk factors for incident infection, the potential risk factors identified from the literature review in Table 9 of this document were modified by subject matter experts o n HIV and hepatitis to create a revised list of risk factors for screening in
Table 3 of this document . The revised list takes into consideration that 1) certain risk factors can be omitted because they are likely markers for other factors identified in th e systematic review and 2) certain risk factors should be added because scientific evidence associating certain factors with the bloodborne pathogens exists, but may not have met the inclusion criteria of the system atic review or studies were of insufficie nt quality to
draw conclusions.

Q 4 .A. HIV and Nonbehavioral Risk Factors

Q 4 .A.1. People with Hemophilia or Related Clotting Disorder who Received Clotting Factor Blood Products

No studies were identified that met the inclusion criteria. The 1994 guidelin e excludes from donating “Persons with hemophilia or related clotting disorders who have received human

- derived clotting factor concentrates.”

Q 4 .A.2. Exposure to Infected or Suspected Infected Blood

No studies were identified that met the inclusion crit eria. The 1994 guideline excludes from donating “Persons who have been exposed in the preceding 12 months to known or suspected HIV

- infected blood through percutaneous inoculation or through contact with an open wound, nonintact skin, or mucous membrane.”

Q 4 .A.3. Children
We did not identify any literature regarding the nonbehavioral risk factors listed above, in children, or in children of mothers who engage in those nonbehavioral risk factors.

Q 4 .A.4. Signs and Symptoms

No studies were identified that met the inclusion criteria. An objective of this section was to identify nonbehavioral factors that could be predictive of infection, especially acute infection during the window period before tests could recognize the infection.61 Additional Risk Factors from 2009 Literature Search

Q 4 .A.5. Receipt of Blood Transfusion

No studies were identified that met the inclusion criteria.

Q 4 .A.6. Nonspecific Exposure

Q4.A.6.a. Accidental Needle Stick A single study found very low quality evidence that did not find an association between accidental needle sticks
and HIV infection. ( Table 42 ) Data was collected from next

- of

- kin for potential corneal donors . The study did not identify if the needle stick occurred in an occupational or nonoccupational setting

. 107 ( Table 41 )

Q 4 .A.6.b. Hemodialysis

No studies were identified that met the inclusion criteria.

Q 4 .A.6.c. Surgery A single study found very low quality evidence which did not find an association between having surgery and acquiring HIV. ( Table 42 ) Data were collected from next

- of

- kin for potential corneal donors. 107 ( Table 41 )

Q 4 .A.6.d. Organ and Corneal Transplantation Recipients
No organ donor studies were identified that met the inclusion criteria. There was very low quali ty evidence which did not find an association between having a corneal transplant with HIV. ( Table 42 ) Receipt of organ transplantation was not associated with a greater risk of HIV in a corneal donor study. 107 ( Table 41 )

Q 4 .A.6.e. Acupuncture

No studies were identified that met the inclusion criteria.

Q 4 .A.6.f. Dental Work

No studies were identified that met the inclusion criteria.

Q 4 .A.6.g. Blood Draws

There was very low quality evidence that did not find an association between having blood drawn and HIV. ( Table 42 ) A corneal donor study did not find an association between blood drawn for HIV testing and HIV, based upon next of

- kin interviews. 107 ( Table 41 )

Q 4 .A.6.h. Other Blood Exposure

No studies were identified that met the inclusion criteria.

Q 4 .A.6.i. Household Exposure

No studies were identified tha t met the inclusion criteria.62 Q 4 .A.7. Other Infections This review found low quality evidence ass ociating HIV with having another infection

. ( Table 42 ) In general population studies, HIV infection was associated with a diagnosis of an STD in one study, 106 herpes simplex
virus

- 2 (HSV

- 2 ) in two studies with large effect size s in univariate analyses, 104

, 105 and syphilis or infection s other than HIV in a fourth study in multivariate analysis. 108 Rabies exposure was not associated with HIV in a
corneal donor study. 107 ( Table 41 ) The prevalence of antibodies to HSV

- 2 was 28% in a general population study co mprising New Yorkers. 105 STD diagnoses were reported by 18% of patients in an urban medical care

center. 106 ( Table 43 )

Q 4 .A.8. Demographic Factors

Q 4 .A.8.a. Sex Three general population studies did not find an association between male sex and HIV, and the evidence was rated low quality

. 105

, 106

, 123 ( Table 41 )

Q 4 .A.8.b. Age or Year of Birth
We found very low quality evidence to suggest a relationship between age and having HIV. ( Table 42 ) Studies
assessed different age ranges , complicating comparison. One study found adults aged 18 to 30 had incr eased prevalence of HIV in a multivariate analysis

. 123 A nother study found higher prevalence of HIV in adults aged
25 to 40 compared to younger people aged 15 to 24 years in univariate analysis with a large effect size, 106 109 and a third found increased prevalence among adults aged 35 to 44 years. 108 ( Table 41 )

Q 4 .A.8.c. Race or Ethnicity, and National Origin We found very low quality evidence to suggest an association between race or ethnicity and HIV . ( Table 42 ) Two general population studies found a higher prevalence of HIV in Asians and Hispanic ethnicity compared to
White race 105

, 106 and those who spoke Spanish compared to English in em ergency room patients. 123 i n univari ate analyses These same stud ies found increased prevalence of HIV with a large effect size among people of Black

race 105

, 106 but a third study in the general population did not. 123 ( Table 41 )

Q 4 .A.8.d. Occupation
No studies were identified that met the inclusion criter i a.

Q 4 .A.8.e

. Education Neither of two general population studies found an association between having less than a high school education and having HIV. 104

, 106 The evidence was rated very low quality. ( Table 41 )

Q 4 .A.8.f. Economic Factors There was very low quality evidence suggesting an association between economic factors and having HIV. ( Table 42 ) Being homeless was independently associated with an increased prevalence of HIV in public hospital emergency room patients 123 while having a poverty index of less than one was not associated with

HIV. 104 ( Table 41 )

Q 4 .A.8.g. Health Insurance Patients with no health insurance had higher prevalence of HIV in one study of hospital patients, 106 but not in another such study. 123 ( Table 41 ) This evidence was rated as very low quality. ( Table 42 )63 Q 4 .A.8.h. Marital Status A single study found low quality evidence to suggest a relationship between marital status and having HIV. ( Table 42 ) Being married or cohabitating was associated with a lower prevalence of HIV in the general population. 104 ( Table 41 )

Q 4 .B. HBV and Nonbehavioral Risk Factors

Q 4 .B.1. People with Hemophilia or Related Clotting Disorder who Received Clotting Factor Blood Products We identified zero studies that studied whether this factor was associated with an increased p revalence of
infection. The 1994 guideline excludes from donating “Persons with hemophilia or related clotting disorders
who have received human

- derived clotting factor concentrates.”

Q 4 .B.2. Exposure to Infected or Suspected Infected Blood
There was ver y low quality evidence supporting exposure to blood known or suspected to be HBV infected as a
risk factor for HBV. ( Table 42 ) The 1994 guideline excludes from donating “Persons who have been exposed in the preceding 12 months to known or suspected HIV

- inf ected blood through percutaneous inoculation or through contact with an open wound, nonintact skin, or mucous membrane.” Among embalmers, no association
was found between needle stick injury with exposure to HBV during embalming and HBV infection. 124 ( Table
39 )

Q 4 .B.3. Children We did not identify any literature regarding the nonbehavioral risk factors, listed above, in children, or in children of mothers who engage in those nonbehavioral risk factors risk factors.

Q 4 .B.4. Signs and Symptoms
No studies were identified that met the inclusion criteria. An objective of this section was to identify nonbehavioral factors that could be predictive of infection, especially acute infection during the window period before tests could recognize the infection.

Additional Risk Factors from 2009 Literature Search

Q 4 .B.5. Receipt of Blood Transfusion There was very low quality evidence to support receipt of blood transfusions as a risk factor for HBV. ( Table
42 ) Although no studies reported on risk in people with clotting disorders or who ha ve received clotting factor blood products, several investigated the risk of infection associated with blood transfusion. Blood transfusion was independently associated with HBV infection in a general population, 112 as was blood transfusion before 1991 among college students. 111 Blood transfusion was not associated with HBV in a low prevalence obstetric patients study. 115 Among volunteers from an urban area, 20% reported having ever had a blood transfusion. 112
( Table 39 ) There was low quality evidence estimating the prevalence of receiving a blood transfusion. ( Table
44 )

Q 4 .B.6. Nonspecific Exposure

Q 4 .B.6.a. Accidental Needle Stick Review of the literature revealed very low quality evidence that did not suggest an association between accidental needle stick and acquiring HBV. ( Table 42 ) In a general population study, needle stick injuries were actually associated with lower prevalence of HBV infection. 11 2 This may be because a substantial proportion of the enrollees were healthcare workers, and in that study healthcare workers had a lower prevalence of HBV than64 the group as a whole. According to data collected from next

- of

- kin, accidental needle sticks were not associated with HBV among potential corneal donors. 107 ( Table 39 )

Q 4 .B.6.b. Hemodialysis We found moderate quality evidence suggesting hemodialysis as a r isk factor for HBV. ( Table 42 )

H emodialysis was associated with HBV among participants in a general population study 112 and college
students 111 with large effect sizes in univariate analyses . ( Table 39 )

Q 4 .B.6.c. Surgery We found very low quality evidence which did not suggest an association between having had surgery and

HBV. ( Table 42 ) In the general population, surgery was associated with a slightly lower HBV prevalence in univariate analysis, 112 and surgery during the last six months was not associated with acute HBV. 116 Based upon

next

- of

- kin data for potential corneal donors, no association was found between HBV and surgeries. 107 ( Table
39 )

Q 4 .B.6.d. Organ and Corneal Transplantation Recipients No organ donor studies were identified that met the inclusion criteria. There was very low quality evidence associating having had a corneal transplant and HBV. ( Table 42 ) Receipt of organ transplan tation was not associated with a greater risk of HBV in a corneal donor study, 107 or with HBV among psychiatric inpatient

veterans. 113 ( Table 39 )

Q 4 .B.6.e. Acupuncture There was low quality evidence which did not s uggest a relationship between acupuncture and having HBV. ( Table 42 ) Acupuncture during the last six months was not associated with an increased incidence of acute HBV in the general population, 116 or an increased prevalence of HBV among psychiatric inpatient veterans. 113
( Table 39 )

Q 4 .B.6.f. Dental Work A single general population study found very low quality evidence which did not suggest an a ssociation
between dental work within the last six months and HBV. 116 ( Tables 42 and 39 )

Q 4 .B.6.g. Blood Draws A single study found very low quality evidence which did not suggest an association between blood draws and having HBV. ( Table 42 ) Blood draws are probably a proxy for other risk factors. A corneal donor study did not find an association between HIV testing and HBV based upon next

- of

- kin interviews. 107 ( Table 39 )

Q 4 .B.6.h. Other Blood Exposure
These factors h ere reported because of their relevance but did not rate the GRADE for these outcomes due to lack of replication of the factors. Neither bloody object contact 113 nor combat exposure 114 were associated with HBV among psychiatric inpatient veterans.

Q 4 .B.6.i. Household Exposure This review found very low quality evidence associating household exposure with someone with HBV and having HBV. ( Table 42 ) Having household contact with someone with hepatitis was associated with HBV among college students, 111 as was a family history of HBV among Asian Americans in multivariate analysis. 125

However, having a household member with HBV was not associated with HBV in an obstetric population; 115 nor was being the wife of a man with HBV among Korean American church goers. 126 Sharing a razor or toothbrush with a household member was not associated with HBV in a general population study. 116 ( Table 39 )65 Q 4 .B.7. Other Infections We found low quality evidence to suggest an association between having HBV and exposure to, or having, other types of infection. ( Table 42 ) Among college students, HBV infection was associated with having had a sexually transmitted disease (STD) in multivariate analysis. 111 Rabies exposure was not associated with HBV in

a corneal donor study. 107 ( Table 39 )

Q 4 .B.8. Demographic Factors

Q 4 .B.8.a Sex We found very low quality evidence to suggest an association between sex and having HBV. ( Table 42 ) Males had higher rates of HBV than females in studies of the general population

, 112 Asian American population in multivariate analys es, 125 and psychiatric inpatient veterans (of whom nearly all were male), 113 but not in studies
of Korean American church goers. 127 Among college students, females had higher rates of HBV in multivariate analysis, 111 A mong children who had received a blood transfusion, rates were not significantly different between genders. 128 ( Table 39 )

Q 4 .B.8.b. Age or Year of Birth There was very low quality evidence to suggest age as a risk factor for HBV. ( Table 42 ) Studies assessed different age ranges , complicating comparison. One general population study found an increas ed risk of HBV in individuals >60 years of age in multivariate analysis. 112 The remaining studies were in demographic or socioeconomic subpopulations . One study of college students found an association with increased mean age in multivariate analysis, 111 while a study of psychiatric inpatient veterans did not. 113 In univariate analyses, increased prevalence was associated with age over 35 years among embalmers in high

- prevalence urban areas
with a l arge effect size 124 and “age younger than 20 years” among Korean

- American church

- go ers, 126 but not age over 50 years among psychiatric inpatient veterans in multivariate analysis. 114 In another study of Korean

American church

- goers, lower prevalence was found in people u nder 49 years. 127 The last study comp rising Asian Americans did not find any association between age and HBV

. 125 ( Table 39 )

Q 4 .B.8.c. Race or Ethnicity, and National Origin This review found very low quality evidence to suggest a relationship between HBV and an individual‟s race, ethnicity or national origin. ( Table 42 ) Regarding race or ethnicity, non

- Hispanic Black race , compared with

non

- Hispanic White race , was associated with a higher prevalence of HBV in a general population, 110 among college students 111

, and psychiatric inpatient veterans in multivariate analyses

. 114 This association was not found
in a study of psychiatric inpatient veterans. 113 Being Mexican

- American was not associated with a different prevalence of HBV than non

- Hispanic White race in a multivariate analysis of a general population study. 110 And in demographic or socioeconomic s ubpopulations , Hispanic ethnicity 113 and Hispanic or Latino ethnicity 111 were not associated with HBV infection. Additionally, White race or Hispanic ethnicity was associated with lower HBV prevalence in a general population study in multivariate analysis. 112 A mong college students

, Asian
students ha d higher rates of HBV. 111 Regarding national origin, H B V was independently associated with being
born in Southeast Asia or Africa in one general population study

. 112 A special population study found children born in Korea had higher prevalence of HBV than children born in the United States

. 126 Other special population studies did not find significantly different rates of Asian Americans born in East Asia (excluding China) or Southeast Asia or Pacific Islands compared to Asian Americans born in China. 125 In a general population study, acute HBV was not associated with birth in an area with a high endemic rate of HBV or having a household contact with someone who was born in an endemic area. 116 In multivariate analyses, a general population study 110 and a study of Asian Americans study 125 found that being born in the United States was associated was lower prevalence of HBV ; the relative odds of HBV comparing “other” national origins to the United States was 3.4

. Among African American, Caucasian, Asian, and Hispanic children who received blood transfusions, the prevalence of HBV was not significantly different. 116 ( Table 39 )66 Q4.B.8.d. Occupation There was low quality evidence supporting an association between the type of occupation and having HBV. It is important to note tha t some of these studies included data on healthcare workers before 1992, when HBV vaccination requirements for healthcare workers took effect. A single study found very low quality evidence showing no association between military service and HBV. ( Table 42 ) Being a healthcare worker with frequent blood exposure was associated with an increased prevalence of HBV in college students, 111 but being a healthcare worker was not associated with HBV in general population studies 110

, 112 or having been a healthcare
worker in psychiatric inpatient veterans. 113 Another general population study did not associate healthcare employment or household contact with someone who is a healthcare worker with HBV, 116 and a special population study did not associate being a healthcare worker or the spouse of one with HBV. 115 Being in the military also was not associated with HBV in a general population study. 110 ( Table 39 )

Q 4 .B.8.e. Education There was very low quality evidence suggesting a relationship between education level and HBV status. ( Table
42 ) Compared to patients with some college education, those with l ess than a high school education had higher prevalence of HBV in multivariate analysis. 110 A second study reported that students enrolled in 4

- year colleges
had lower rates of HBV than students enrolled in 2

- year colleges in multivaria te analysis. 111 However, years of
education was not associated with HBV among psychiatric inpatient veterans. 113 ( Table 39 )

Q 4 .B.8.f. Economic Factors We found very low quality evidence which did not find an association between economic factors and HBV. ( Table 42 ) Being homeless was not associated with an increased risk of HBV among psychiatric inpatient

veterans. 113 Another special population study did not associate homelessness, institutionalization, or other non

independent livin g arrangement with HBV. 114 ( Table 39 )

Q 4 .B.8.g. Health Insurance
No studies were identified that met the inclusion criteria.

Q 4 .B.8.h. Marital Status We found low quality evidence to support marital status as a risk factor for HBV . ( Table 42 ) A genera l population study reported that b eing divorced or single was associated with a higher prevalence of HBV than any other status in multivariate analysis. 110 Being currently married was not associated with any difference in HBV prevalence than any other status among psychiatric inpatient veterans. 11 4 ( Table 39 )

Q 4 .C. HCV and Nonbehavioral Risk Factors

Q 4 .C.1. People with Hemophilia or Related Clotting Disorder who Received Clotting Factor Blood Products
We identified zero studies that studied whether this factor was associated with an increased prevalence of
infection. The 1994 guideline excludes from donating “Persons with hemophilia or related clotting disorders
who have received human

- derived clotting factor concentrates.”

Q 4 .C.2. Exposure to Infected or Suspected Infected Blood
No studies were identified that met the inclusion criteria. The 1994 guideline excludes from donating “Persons who have been exposed in the preceding 12 months to known or suspected HIV

- infected blood through percutaneous inoculation or through contact with an open w ound, nonintact skin, or mucous membrane.”

Q 4 .C.3. Children We did not identify any literature regarding the nonbehavioral risk factors, listed above, in children, or in children of mothers who engage in those nonbehavioral risk factors risk factors.67 Q 4 .C.4. Signs and Symptoms Review of the outlined studies found low quality evidence associating HCV with jaundice, alanine
aminotransferase (ALT) reactivity, and elevated ALT with large effect sizes. There was very low quality evidence associating HCV with elevated liver enzyme and t he effect size was not large

. ( Table 42 ) There was low quality evidence regarding the prevalence of sign and symptoms for HCV ( Table 44 ) An objective of this section was to identify nonbehavioral factors that could be predictive of infection, especially acute infection during the window period before tests recognize the infection. Four studies were identified. 51

, 109

, 119

, 121 In blood donors, ALT reactivity was significantly associated with infection with a large magnitude of effect. 119 In a general population, serum ALT of >40 U/L was associated with HCV. 51 E levated liver enzyme s w ere sig nificantly associated with HCV with a large effect size in adults, comprising individuals at risk for HCV and healthcare workers, enrolled in a HMO. 109 In addition, jaundice was associated with HCV in adults in a general medical clinic with a large effect size. 121 A ll four were univariate analyses. ( Table 40 ) In one study, 9% of respondents had ALT levels >40 U/L. 51 ( T able 43 ) and evidence was rated low quality

.

Additional Risk Factors from 2009 Literature Search

Q 4 .C.5. Receipt of Blood Transfusion We found moderate quality evidence supporting an association between receiving blood transfusions and HCV with a large effect size. ( Table 42 ) Although no studies reported on risk in people with clotting disorders or who have received clotting factor blood products, many did investigate the risk of infection associated with blood transfusion. All eight studies found some association with transfusion and HCV infection. Receiving a blood transfusion was independently associated with HCV in three blood donor s tudies (data collection occurring
1994

- 96, 1991, and 1992

- 93) 117

, 120

, 129 and three general population studies (data collection occurring 1999

- 2002, 2000

- 2002, and 1992)

. 51

, 112

, 118 t he remaining two general population study performed univariate analyses. 109

, 121 In a study of blood donors, sex with a blood transfusion recipient was also associated with
HCV. 117 Additionally, a significan t association was found between blood transfusion and HCV among donors who had never injected drugs. ( Table 40 ) Among general population survey respondents, 6% aged 20 to 59 years and 16% of those aged at least 60 years reported having a blood transfusion before 1992. 51 Among volunteers from an urban area, 20% reported having ever had a blood transfusion. 112 ( Table 43 ) We found low quality evidence regarding estimates of the prevalence of having blood transfusions. ( Table 44 )

Q 4 .C.6. Nonspecific Exposure

Q 4 .C.6.a. Accidental Needle Stick There was very low quality evidence supporting accidental needle stick as a risk factor for HCV. ( Table 42 ) In a general population study, needle stick injuries were actually associated with lower prevalence of HCV
infection. 112 This may be because a substantial proportion of the enrollees were healthcare workers, and in that study healthcare workers had a lower prevalence of HCV and HBV than the group as a whole. Needle st ick injuries among healthcare worker blood donors were not associated with HCV either. 120 However, bloody
needle stick injuries in a medical setting was independently associated with an increased prevalence of HCV. 117 According to data collected from next

- of

- kin, accidental needle sticks were not associated HCV among potential corneal donors. 107 ( Table 40 )

Q 4 .C.6.b. Hemodialysis There was low quality evidence which found an association between hemodialysis and HCV. ( Table 42 ) In two general population studies, HCV infection was independen tly associated with hemodialysis 112 and with “kidney dialysis” in univariate analysis with a large effect size. 121 A third study involving adults with known HCV, risk68 factors for HCV, or planned hemodialysis did not fi nd an association between hemodialysis and HCV in univariate analysis. 118 ( Table 40 )

Q 4 .C.6.c. Surgery We found very low quality evidence supporting having had surgery with HCV infection. ( Table 42 ) In a univariate analysis, being hospitalized was associated with HCV with a large effect size; however, having surgery or a medical procedure in the six months before blood donation was not associated with HCV. 119 Having a history of surgery was not associated with HCV in general population studies. 109

, 112 However, lifetime
h istory of surgery or sutures was independently associated with elevated HCV prevalence in blood donors. 117 Based upon next

- of

- kin data for potential corneal donors, no associations was found between HCV and surgeries. 107 ( Table 40 )

Q 4 .C.6.d. Organ and Corneal Transplantation Recipients No organ donor studies were identified tha t met the inclusion criteria. A single study found very low quality evidence to suggest an association between having a corneal transplant and HCV. ( Table 42 ) Receipt of organ transplantation was not associated with a greater risk of HCV in a corneal donor study. 107 ( Table 40 )

Q 4 .C.6.e. Acupuncture There was low quality evidence which did not find an association between acupuncture and HCV ( Table 42 ) among blood dono rs, 120

, 129 or people in a general population study. 118 ( Table 40 )

Q 4 .C.6.f. Dental Work There was low quality evidence which did not suggest an association between having dental work and HCV. ( Table 42 ) Dental work was not associated with HCV among blood donors, 117 nor was having dental work in
the six months before blood donation. 119 ( Table 40 )

Q 4 .C.6.g. Blood Draws We found very low quality evidence suggesting an association between having blood drawn and HCV infection. ( Table 42 ) A general population study reported an association between having had a blood test for HBV and having an HCV infecti on in univariate analysis with a large effect size. 121 In the same study, being a blood donor was associated with reduced risk of HCV, and having been rejected as a blood d onor was associated with an increased risk of HCV, also with a large effect size. 121 Based upon next

- of

- kin data for potential corneal donors, no associa tions was found between HIV testing and HCV. 107 ( Table 40 )

Q 4 .C.6.h. Other Blood Exposure
These factors w ere reported because of their relevance but G RADE ratings w ere not done due to lack of replication of the factors. Having been stuck or cut with a bloody object was independently associated with HCV among blood donors. 129 Among blood donors, blood exposure during fighting, by biting, at an accident
si te, or during a manicure in the last six months was associated with HCV in univariate analysis with a large effect size, but not during a haircut in the last six months. 119 Contact with blood was not associated with HCV in members of a general population. 118 ( Table 40 )

Q 4 .C.6.i. Household Exposure We found very low quality evidence to suggest a relationship between household ex posure to HCV and having
HCV. ( Table 42 ) Among blood donors, living with someone with hepatitis or having a relative with hepatitis was not associated with HCV infection, but in multivariate analysis living with a transfusion recipient was. 117 Additionally, sharing a toothbrush or razor with person(s) unspecified was associated with HCV among blood
donors. 117 In general population studies, having at least one family member treated for viral hepatitis was not69 associated with an increased risk of HCV in one study, 109 but having at least one family member with HCV was associated with an increased risk in another study. 121 ( Table 40 )

Q 4 .C.7. Other Infections We found low quality evidence to suggest an association between STD or other infections and having HCV. ( Table 42 ) We found moderate quality evidence estimating the prevalence of HSV

- 2 infection. ( Table 44 ) Among blood donors, HCV was significantly associated with history of STD, 117

, 120 having a STD wi thin six months of donating, 119 and seropositivity for other reactive infectious diseases 119

, 129 with two of the studies demonstrating an independent association. 117

, 129 Among people from general populations, having past treatment for STDs was not associated with HCV, 121 but having HSV infec tion was. 51 HIV infection was not associated
with HCV infection in univariate analysis of a general popul ation. 1 18 Rabies exposure was not associated with
HCV in a corneal donor study. 107 ( Table 40 ) Antibodies to HSV

- 2 were detected in 19% of general nationwide population aged 18 to 49 years. 51

Q 4 .C.8. Demographic Factors

Q5.C.8.a. Sex We found very low quality evidence to suggest an association between gender and having HCV. ( Table 42 )

B eing male was independently associate d with an increased risk of HCV a mong heart transplant donors 122 and blood donors, 129 but was not associated in two blood donor studies. 119

, 120 In the general population, significantly higher proportions of males had HCV infection in four 51

, 112

, 121

, 130 out of five studies. 109 ( Table 40 )

Q 4 .C.8.b. Age or Year of Birth
There was ve ry low quality evidence associating age and HCV. ( Table 42 ) Studies assessed different age

ranges , complicating comparison. An organ donor study found that HCV infection was associated with older median age. 122 One blood donor study associated HCV with older mean age, 119 while the other did not. 120 In general population studies, HCV was associated with increased mean age 130 and decade of birth (with people born between 1940 and 1959 having the highest prevalence), 121 but not age less than 50 years 109 or age less than 60 years. 112 ( Table 40 )

Q 4 .C.8.c. Race or Ethnicity, and National Origin Review of the outlined studies found very low quality evidence associating H CV with an individual‟s race or ethnicity, as well as very low quality evidence associating HCV with national origin/birthplace and preferred language ( Table 42 ) Among heart donors, ethnicity was not associated with HCV. 122 Black race was associated with increased rates of HCV compared to White race in two blood donor studies, 120

, 129 of which one was an independent finding. 129 In general population studies, Black race or Hispanic ethnicity was independently associated with infection in one study; 51 however, Black race or Hispanic ethnicity was not associated with
infection in two other studies. 121

, 130 Among blood donors, one study found that Hispanic ethnicity had a higher
risk of HCV than White race in multivariate analysis, 129 but another did not. 119 Being Asian was associated with having a lower prevalence of HCV compared to White race among blood donors in multivariate analysis. 129 One blood donor study did not associate foreign birth with HCV, 119 but another did in multivariate analysis. 129 A general population study found p eople born outside of the U.S. had a lower prevalence of HCV in multivariate analysis. 51 Birth in Southea st Asia or Africa was not associated with an increased prevalence of HCV in another general population study. 112 Another general population study found no association between HCV and U.S. citizenship. 121 Among African American, Ca ucasian, Asian, and Hispanic children who received blood transfusions, the prevalence of HCV was not significantly different. 112 ( Table 40 )70 Q 4 .C.8.d. Occupation We found very low quality evidence to support an individual‟s type of occupation as being a risk factor for
HCV. ( Table 42 ) Among blood donor s, occupational blood exposure was independently associated with HCV infection, 117 but a medical or dental job or public safety job with frequent blood contact was no t. 119 In the general population, work contact with blood was not associated with increased HCV, 109 and being a healthcare
worker was associated with a lower rate of HCV. 112 In two general population studies, having served in the
armed forc es was not associated with HCV. 51

, 109 A study of health clinic patients did associate having a job at a prison with having HCV. 121 ( Table 40 )

Q 4 .C.8.e. Education There was very low quality evidence suggesting an association between level of education and HCV infection. ( Table 42 ) Lower educational attainment was associated with HCV in blood donors 119

, 120 with one study having a large effect size in univar iate analysis. 119 One general population study associated having fewer than 12 years of education with having HCV, 51 but two others found no association between educational attainment and
HCV. 121

, 130 ( Table 40 )

Q 4 .C.8.f. Economic Factors There was very low quality evidence associating economic factors and HCV. ( Table 42 ) Ever having been
homeless was associated with an i ncreased risk of HCV in adults attending general medicine or hepatology
clinics. 121 Neither income nor living in poverty was associated with HCV

. 51

, 121 ( Table 40 )

Q 4 .C.8.g. Health Insu rance A single study found very low quality evidence to suggest an association between type of health coverage (Medicaid, Medicare, private, or self

- pay) and having HCV ( Table 42 ) , with Medicaid patients having the highest prevalence of HCV. 130 ( Table 40 )

Q 4 .C.8.h. Marital Status A single study found low quality evidence associating marital status and HCV. ( Table 42 ) Being married was
associated with a lower rate of HCV in one blood donor study. 117 ( Table 40 )



### Question 5 . What are the test characteristics of the screening methods available to detect HIV, HBV
, and HCV in potential solid organ donors? Do test characteristics differ in particular populations and with donor clinical status (i.e., donation after brain death
versus donation after cardiac death OR adult versus pediatric donors)?

Numerous tests exist to detect HIV, HBV and/or HCV in potential donors, and this question concerns the

accuracy , sensitivity, and specificity of those tests, as well as the length of the window period and the turnaround time to perform the tests. For the systematic review of the literature, t ests of interest include d immunoassay tests and NAT currently used in the United States by OPOs, as well as fourth

- generation HIV and HCV antibody/antigen tests currently in use outside of the United States. Other FDA licensed assays, such as the Abbott Prism HCV, Procleix Ultrio Assay and Abbott Prism HIV O Plus were not included for review as these assays are not routinely used by OPOs. T he p24 antigen test for HIV was not included because it is no longer used by OPOs. Additionally, a n HC V antigen assay used in Europe was not included because the assay was licensed subsequent to the guideline literature search

.

Initial searches of bibliographic databases were for test instruments for HBV, HCV, or HIV. Once the list of included tests was g enerated, additional searches were performed specifically by each test‟s name. The focus of71 these searches was to identify peer

- reviewed literature regarding window period, turnaround time, and test performance characteristics. Because this strategy did no t identify information for all of the listed tests, we also
searched other literature sources, including FDA product labeling information

, package inserts

, manufacturer‟s Web sites, and additional sources including the World Health Organization

. FDA approv al information was searched for all tests as well. We used these sources for information on turnaround time and window period but
not other test characteristics (e.g., sensitivity and specificity), because these sources of information generally do
not repo rt sufficient information to enable assessment of the study design, quality, and other factors that impact the outcomes and the strength of the evidence. Where data from sources other than clinical literature were used for the other characteristics, the so urce is clearly noted in the Evidence Report extraction tables.

The window period is particularly important in this context because a recently infected potential organ donor who is tested using immunoassays only would not be diagnosed prior to donation of solid organs. The information regarding window periods is derived from testing seroconversion panels ( series of blood draws from patients who eventually become seropositive ) . A limitation of the panels is that the samples are not typic ally collected daily but at irregular intervals. Furthe r more, studies generally reported the difference in window period between two tests (e.g., Test 2 detected infection an average of # days later than Test 1). Therefore, information captur ing absolute w indow periods was unavailable . Information on the time required to fully administer tests was sparse. Window period and turnaround time were not assessed using GRADE because
information often came from sources other than peer

- reviewed publications

. No stud ies reported on positive predictive values (PPV) or likelihood ratios. There were no studies comparing test characteristics between different donor populations. Although a large number of peer

- reviewed publications and pieces of gray
literature were includ ed, little (or no) data addressed each individual stud y of interest. None of the studies focused on pediatric use.

Q5.A. HIV

Immunoassays and Nucleic acid tests (NAT) currently in use by U.S. OPOs

Q5.A.1 HIV 3rd generation immunoassays We found low qua lity evidence addressing the sensitivity and specificity of third generation immunoassay tests. ( Table 56 ) Test sensitivity and specificity were calculated in two analytic studies with a sensitivity of 99.4

- 100% and specificity of 97.7

- 99.7%. 131

, 132 ( Table 55 ) Seroconversion panels showed positive responses ranging from the same day to about 14 d ays sooner than Western blot

. 131

- 134 ( Tables 52 and 54 ). No data were found on
the duratio n of time required for the test to be performed (turnaround time).

Q5.A.2. HIV NAT We found low quality evidence regarding the sensitivity and specificity of NAT assays. ( Table 56 ) Test sensitivity and specificity were calculated in analytic and clinical studies with a sensitivity range of 92.6

- 100% and a specificity range of 96.9

- 100%. These studies included individual and HIV/HCV combined assays.

132

, 135

, 136 ( Table 55 ) NAT results were positive ranging from 2

- 24.5 days before antibody assays. 135

, 137

- 141 NAT
results were reactive from 0

- 28 days before antigen tests 135

, 137

, 138

, 140

, 141 ( Tables 52 and 54 ) One study reported a
turnaround time of two hours for HIV alone testing, 142 whereas another reported that an experienced operator required 6 hours to p erform two HIV/HCV combined assays and 6.5 hours to perform three HIV/HCV combined assay s

. 137 ( Tables 51 and 54 )

Immunoassays currently not in use by U.S. OPOs

Q5.A.3. HIV 4 th generation immunoassays72 There was low to moderate quality evidence that examined the specificity and sensitivity accuracy of fourth generation EIA tests. ( Table 56 ) Test sensitivity and specificity were calculated in five analytic and three clinical studies with a sensitivity of 100% 143

- 149 and a specificity range of 82.5

- 100%. 143

- 145

, 147

- 152 ( Table 55 )
Five studies reported differences in window period time from third generation antibody and polymerase chain
reaction ( PCR ) assays using seroconversion panels. ( Tables 52 and 54 ) Fourth generation assays were reactive ranging from 0

- 6.15 days before third gener ation antibody assays. 144

, 147

- 149

, 153

, 154 Howe ver, when compared with NAT, fourth generation assays were reactive ranging from 2.31

- 2.75 days after RT

- PCR

. 149

, 153 ( Table 10 ) Turnaround time ranged from 26 minutes to 4 hours depending on the test brand. ( Tables 51 and 54 )

Q5.B. HBV

Immunoassays and Nucleic acid tests (NAT) currently in use by U.S. OPOs

Q5.B.1. HBsAg
This review found low to moderate quality evidence regarding the sensitivity and specificity accuracy of HBsAg assays. ( Table 56 ) Test sensitivity and specificity were calculated in analytic and clinical studies with a sensitivity of 100% and a specificity of 97.9

- 99.4%. 155

, 156 ( Table 55 ) HBsAg detected reactive results 0

- 7 days
earlier than unnamed licensed reference s

. 157

- 159 ( Tables 52 and 54 ) Two studies reported a turnaround time of
29

- 30 minutes. 63

, 146 ( Tables 51 and 54 )

Q5.B.2. Anti

- HBs Our search did not identify any studies examining anti

- HBs sensitivity and specificity. In one study of 40 seroconversion panels, the anti

- HBs assay was reactive a me dian of 14

- 18 days after the NAT method. 160 In another study, the window period for the HBsAg and anti

- HBs assays were the same for 10 of 21 seroconversion panels with anti

- HBs reactivity occu rring later for the remaining 11 pan els. 161 ( Tables 52 and
54 ) No studies reported on the turnaround time for performing the test.

Q5.B.3. Anti

- HBc Our search did not identify any studies examining anti

- HBc sensitivity and specificity accuracy. In one study of 7 seroconversion panels, the anti

- HBc assay detected in fection at the same time as an unnamed reference in 6 panels and one day sooner in the seventh. 162 Per product label, anti

- HBc appears in the serum of patients
infe cted with HBV one to four weeks after the appearance of HBsAg, at the onset of symptoms. 163 ( Tables 52
and 54 ) No studies reported on turnaround time for performing the test.

Q5.B.4. HBV NAT
We found very low quality evidence regarding the s ensitivity and specificity of NAT assays. ( Table 56 ) Test sensitivity and specificity were calculated in one clinical study with a sensitivity of 84.8% and specificity of
100%. 164 ( Table 55 ) NAT assay were reactive 10

- 20 days before HBsAg. 160

, 165 ( Tables 52 and 54 ) No studies reported turnaround time for conducting the test.

Q5.C. HCV

Immunoassays and Nucleic acid tests (NAT) currently in use by U.S. OPOs

Q5.C.1. HCV 2 nd or 3 rd generation immunoassays
There was moderate quality evidence demonstrating the sensitivity and specificity of second and third generation immunoassays . ( Table 56 ) Test sensitivity and specificity were calculated in clinical studies with test sensitivity of 73.2

- 100% and specificity of 92.7

- 99.9% in second generation assays 166

- 168 and test sensitivity of
100% and a specificity range of 94.4

- 99.9% in third generation assays

. 169

- 172 ( Table 55 ) Of 19 blood donors who73 were RNA

- positive but initially negative by a second generation immunoassay, second generation assays were positive a median of 34

- 63 days later. 173 . A third generation assay was positive a mean of 26

- 32 days before second generation assays. 174

, 175 ( Tables 52 and 54 ) No studies reported turnaround time for conducting the test.

Q5.C.2. HCV NAT We found low quality evidence regarding the sensitivity and specificity of NAT assays ( Table 56 ) Test sensitivity and specificity were calculated in analytical and clinical studies with a sensitivity of 99.3

- 99.6% and a specificity of 97.4

- 99.6%. These studies comprised individual and HIV/HCV combined assays. 135

, 136

, 142
( Table 55 ) HCV NAT was reactive a mean of 32

- 85 days before third generation antibody assays; 137

, 175

, 176

, a mean of 113 days before a second generation assay; 176 and a mean of 5 days before a 4th generation test. 177
( Tables 52 and 54 ) One study reported a turnaround time of 2 hours to perform the test. 142 ( Tables 51 and 54 )

Immunoassays currently not in use by U.S. OPO s

Q5.C.3. HCV 4 th generation immunoassays Our search did not identify any studies regarding the sensitivity and specificity of fourth generation immunoassays

. A f

ourth generation assay was reactive a mean of 21.6

- 26 days before 3rd generation

assay s

. 177

, 178 F ourth generation assay s were reactive a mean of 4.8

- 30 days after NAT. 178

, 179 ( Tables 52 and 54 ) One study reported a turnaround time of 190 minu tes to perform the test. 179 ( Tables 51 and 54 )

Questions 3, 4, and 5 Recommendations

3/4.A. To ascertain whether potential organ donors are average risk or at increased risk for having HIV, HBV, or HCV, prospective living donors and next

- of

- kin, as well as individuals familiar with deceased donors (i.e., life partners, cohabitants, friends, healthcare provider),
should be interviewed in a confidential and sensitive manner about behaviors that may have
increased the potential donor ‟s probability of HIV, HBV or HCV infection

. (Refer to Table 3 for risk factors) (Category IB) (Questions 3 and 4 )

3.A. Deceased p otential organ donors also should be screened for HIV using NAT or the most sensitive test available regardless of risk of having HIV and regardless of time relative to procurement (i.e., Donor specimens should be obtained before procurement; however, NAT
results should be obtained either before, if timing allows, or afte r procurement)

. (Category IB) (Question 3)

3.B. Deceased p otential organ donors reported to have behavioral or nonbehavioral factors during the previous 12 months identifying them as being at increased risk for having HBV also
should be screened with HBV NAT or the most sensitive test available, in addition to routine serologic testing and regardless of time relative to procurement (i.e., Donor specimens should be obtained before procurement; however, NAT results should be obtained either before, if timing allows, or after procurement) . (Refer to Table 3 for risk factors) (Category IB) (Question 3)

3/4.B. Children with any risk factors associated with increased probability of HIV, HBV or
HCV should be identified as having an increased probability of HIV, H BV or HCV infection

. (Category IB) (Questions 3 and 4)74

3/ 4.C. Children ≤ 2 years of age born to mothers with HIV, HBV, or HCV infection or mothers
who meet the behavioral or nonbehavioral criteria for increased probability of infection (regardless of their HIV, HBV or HCV status) should also be identified as having an increased probability of HIV, HBV or HCV infection

. (Category IB) (Questions 3 and 4)

4.A. When reviewing medical records, OPO findings consistent with HIV, HBV, or HCV ( e.g

. , mention of a positive test and/or risk factors for infection) in the deceased potential donor should be reported to the transplant center receiving the organ offer

. (Category 1B) (Question 4)

3 /4.D. When a deceased potential organ donor ‟s behaviora l/medical history questionnaire
cannot be obtained or behavioral and nonbehaviroal risk factors cannot be determined, donor NAT screening or the most sensitive test available for HBV should be performed

. (Category IB) (Questions 3 and 4)

5.A. Screening t e st s for HBV (i.e., HBsAg, a nti

- HBc ), HCV (i.e., anti

- HCV), and HIV (i.e.,
anti

- HIV 1/2) should be performed on all potential organ donors (living or deceased). (Category I) (Question 5)

Table 9 lists the factors identified from the evidence in the literature review that were associated with an increased likelihood of HIV, HBV or HCV infection. Given the paucity of literature identifying risk factors for incident infection, the potential risk factors in Table 9 were reviewed with subjects matter expe rts on HIV and hepatitis to create a revised list of risk factors (Table 3) that would facilitate screening out incident (recent) HIV, HBV, or HCV infections in potential organ donors. Table 3 supplant s the identified factors in Table 9

.

Table 9 . Behavi oral Characteristics Associated with HIV, HBV, or HCV Identified by Low to High Quality Evidence from the Systematic Review

HIV ● MSM

● IDU

● N on

- injection illicit drug use

● M ultiple sex partners

● S ex with p artner known to be HIV infected

● A ge ≤ 18 years at first sexual intercourse

HBV ● MSM

● IDU

● M ultiple sex partners

HCV ● IDU

● Non

- injection illicit drug use

● Multiple sex partners

● Sex worker

● Inmates

● Age ≤ 18 y ears at first sexual intercourse

● Sex with partner known to be HCV infected

● S ex with IDU

● Tattooing performed by nonprofessional75

Nonbehavioral Characteristics Identified by Low to High Quality Evidence from the Systematic
Review

HIV ● STD

● Marital status

HBV ● Hemodialysis

● STD

● Marital status

HCV ● Hemodialysis

● Receipt of blood transfusion

● Signs and symptoms (i.e., jaundice, elevated ALT)

● STD

● Marital status

TOPIC III: DONOR INTERVENTIONS TO DECREASE TRANSMISSION OF HIV, HBV, OR HCV
FROM INFECTED DONORS (Question 6)



### Question 6 . Which donor interventions reduce the probability of pathogen transmission from an organ donor infected with HIV, HBV
, or HCV to a previously uninfected recipient?

Q6.A. A single study found low quality evidence regarding interventions to diminish the risk of viral
transmission from infected donors to uninfected rec ipients. 180

, 181 ( Table 60 ) Only one study met the inclusion
criteria. 180

, 181 The 1994 study described perfusion techniques to potentially inactivate virus in kidneys procured
from HCV

- positive deceased donors. The virus

- reducing capacity of four inactivation protocols was investigated with the viral burden ranging from 69% to 99.7%. The response appeared to be dose dependent (i.e., the longer the inactivation procedure, the greater the viral load reduction) . ( Table 58 )

Question 6 Recommendations

6.A. Further research is needed to assess inter ventions (e.g., pathogen reduction methods) to reduce or eliminate the viral burden of HIV, HBV, and HCV in donor s or donor organs before or after recovery. (No recommendation/unresolved issue) (Question 6)

TOPIC IV: POTENTIAL RISKS AND BENEFITS OF TRANSPLANTANTING, OR NOT TRANSPLANTING, SOLID ORGANS FROM DONORS POSITIVE FOR HIV, HBV OR HCV (Question 7)



### Question 7 . How do the clinical outcomes of recipients of organs from donors infected with HIV, HBV or HCV compare to those who remain on the trans plant list?

This question involves whether patient survival will be better if an organ from a donor infected with HIV, HBV

, or HCV is transplanted or the patient remains on the waiting list for an organ from an uninfected donor. Due to
the lack of evidenc e, the initial inclusion criteria was expanded to 1) compar e results of organ transplant s from76 infected and uninfected donors into recipients who were uninfected pre

- transplant and 2) compar e results of

organ transplant s from infected and uninfected donors into recipients who were infect ed pre

- transplant. The use of organs from infected donors may be more acceptable for recipients who are infected pre

- transplant (although

co

- infection with a different genot y pe is possible). Of 22 publications, there were 17 unique studies. None of the studies were randomized or prospective, but all 17 treated the groups concurrently, and 13 studies enrolled patients consecutively. Ten studies (two of HBV and eight of HCV) reported specific baseline patient
characteristics to enable a comparison. Of the differing pre

- transplant characteristics, four of the studies performed statistical adjustments of the results. 75

, 78

, 182

- 184 There were no studies that met inclusion criteria for HIV likely due to OPTN policy that prohibits using organs from HIV infected donors.

Q7.A. HBV Q 7 .A.1. Receivi ng Organs from HBV

- p ositive Donors Compared to Remaining on the Waitlist
No studies were found t hat met the inclusion criteria.

Q 7 .A.2. Receiving Organs from HBV

- p ositive Donors Compared to Organs from Negative Donors When the Recipients were Negative Before Transplant Review of one available study 77 revealed very low quality evidence comparing outcom es of receiving kidneys
from HBV

- positive versus HBV

- negative donor s when recipients are negative pre

- transplant. HBV positivity
was defined as anti

- HBc positive and HBsAg

- negative

. ( Table 63 ) Both patient and graft survival favored receiving a kidney from a n e gative donor in univariate analysis

. ( Table 68, Figure 12 ) T he study did not find

any pre

- transplant differences between HBV

- positive and HBV

- negative donor groups , except for substantially higher rates of stroke among HBV

- positive donors ( Table 66 ).

Q 7 .A.3. Receiving Organs from HBV

- p ositive Donors Compared to Organs from Negative Donors When the Recipients were Positive Before Transplant We found very low quality evidence from studies comparing patient and graft survival outcomes for HBV

positive ca ndidates who received organs from HBV

- positive versus HBV

- negative donors. ( Table 63 ) There

were t hree observational studies of renal transplant recipients where the donor was a nti

- a nti

- HBc

- positive, HBsAg

- negative, 77 IgG a nti

- HBc

- positive, IgM a nti

- HBc

- negative, HBsAg

- negative, 75 and HB sAg

- positive, 185

-

187 and one of liver transplant recipients where the donor was a nti

- HBc

- positive

. 188 Figure 13 shows no consistent trend in patient or graft survival outcomes. One study in kidney transplant recipients found significantly improved graft survival using HBsAg

- posit i ve donor s if the donor was living, and using HBsAg

negative donor s if the donor was deceased. 185

- 1 87 The remaining kidney and liver studi es found no statistically significant differences in graft survival

. 77

, 188 When restricting the analysis to the two studies that used statistical adjustments to control for baseline prognosis, 75

, 77 one study found poorer graft survival in the positive donor

group, 75 and the other study found no large differences in either graft survival or patient survival. 77 ( Table 68 ) The main difference in baseline characteristics included higher rates of HCV, older donor and recipient ages, and more African Americans donors ( Tables 62 and 66 ) in the HBV

- positive donor compared to HBV

- negative
donors. ( Tables 62 and 6 6 ) Of three studies that reported patient survival, only one reported a statistically significant difference. Patient survival was higher in recipients receiving a kidney from an HBsAg

- positive donor if the donor was deceased, but no statistical difference if the donor was living. 185

- 187 Of the two studies that adjusted for potential confounding, 75

, 77 one study found poorer graft survival in the HBV

- positive donor

group, 75 and the other study found no significant differences i n either graft or patient survival. 77 ( Table 68 )

Q7.B. HCV Q 7 .B.1. Receiving Organs from HCV

- p ositive Donors Compared to Remaining on the Waitlist
Review of one observational study 189 found very low quality evidence comparing survival outcomes for patients receiving an HCV

- positive organ versus remaining on the waitlist. ( Table 63 ) This study included patients with77 end

- stage renal disease who had been on the transplant waiting list from April 1995 to August 2000, and were followed to August 2001. The adjusted hazard ratio of 0.76 was statistically significant favoring receipt of a kidney from an HCV

- positive donor versus remaining on the transplant waitlis t. An analysis comparing receipt of a kidney from any deceased donor (regardless of donor HCV status) and being on the waitlist favored transplantation substantially (adjusted hazard ratio of 0.47).

Q7.B.2. Receiving Organs from HCV

- positive Donors Compa red to Organs from Negative Donors When the Recipients were Negative Before Transplant There was low quality evidence on patient and graft survival outcomes from studies comparing receiving organs
from HCV

- positive versus HCV

- negative donors when recipient s were nega tive pre

- transplant. ( Table 63 ) Four observational study involved HCV

- infected donors. 37

, 44

, 99

, 101

, 182

, 183

, 190

, 191 Results for patient survival favored receiving an organ from a n HCV

- negative donor in two studies of heart and kidney donors ; 99

, 101

, 182

, 183 a third study involving liver donors found no statistical difference 24 months post

- transplant ). 37

, 44 Three of the four
studies report ing on liver graft survival found no statistically significant difference 24

- 60 months post

transplant

. 37

, 44

, 182

, 183

, 190

, 191 O nly one study reported baseline characteristics to enable comparison . There were

m ore male donors and older mean recipient age in the positive donor group. 99

, 101 T he rep orted hazard ratio of 2.8 was not indicated as adjusted or unadjusted. 99

, 101 Another s tudy , which adjust ed for pre

- transplant
differences

, 182

, 183 found a significantly shorter survival in those who received organs from HCV

- positive donors. ( Table 66 ) T he difference in baseline characteristics, and the possibility that the pre

- transplant prognosis may have been poorer for recipients who received organs from infected donors make it difficult to interpret these raw results. All study results app ear in Table 68 and Figure 12.

Q 7 .B.3. Receiving Organs from HCV

- p ositive Donors Compared to Organs from Negative Donors When the Recipients were Positive Before Transplant We found very low quality evidence on patient and graft survival outcome s from st udies that compared receipt of organs from HCV

- positive versus HCV

- negative donors when recipients were positive pre

- transplant. ( Table
63 ) Six observational studies addressed kidney transplantation 182

, 183

, 192

- 196 and seven addressed liver transplantati on. 37

, 44

, 184

, 188

, 190

, 191

, 197

- 199

, For kidney ( Figure 14 ) and liver transplants ( Figure 15 ), data suggest a small but consistently better graft survival with HCV

- positive donors than HCV

- negative donors; however, the studies may not have been powered to detect a statistical difference . Of the 11 studies that reported patient survival, one study favored recipients of organs from negative donors, 182

, 183 and the other study favored recipients or organs from HCV

- positive donors 184 (sta tistical adjustments were applied to control for baseline differences). The remaining 9 studies found no significant difference. 37

, 44

, 184

, 188

, 192

- 195

, 197

- 199 Of the 13 studies that reported graft survival,

, 37

, 44

, 182

- 184

, 188

, 190

- 199 significant difference were reported. ( Table 68 ) The baseline characteristics between groups differed; donor/recipient ages were older and the recipient‟s time on the waitlist

was shorter in HCV

- p ositive donor groups. 192

, 193 ( Tables 62 and 66 )

Question 7 Recommendations

7.A. Transplantation of a liver allograft from an HBV

- infected donor into an HBV

- infected transplant candidate may be considered when risk

- benefit is considered favorable by the patient
and transplant center. (Category IIB) (Question 7)

7.B. Transplantation of a liver allograft from an HBV

- infected donor into an HBV

- uninfected transplant candidate should be avoided unless the risk to the recipient of not performing the transplant is elevated and deemed to be greater than the risk of disease development . Should liver transplantation occur, strategies to further minimize this risk should be considered (e.g., HBV vaccination of the transplant candidate, hepatitis B immune globulin, and anti

- vira l78

therapy). (Category IB) (Question 7)

7.C. Transplantation of a non

- hepatic organ from an HBV

- infected donor into an HBV

uninfected transplant candidate may be considered when risk

- benefit is considered favorable by
the patient and transplant center. (C ategory IIB) (Question 7)

7.D. When allografts from HBV

- infected donors are utilized, transplant centers should obtain
informed consent from the patient regarding the probability of HBV transmission and implement strategies to further minimize the consequences of acquiring an HBV infection, as appropriate (e.g., HBV vaccination of the transplant candidate if a nti

- HBs negative; hepatitis B immune globulin

, and anti

- viral therapy)

. (Category IB) (Question 7)

7. E

. The use of a non

- hepatic organ from a n IgG a nti

- HBc positive only donor may be considered for transplantation, as a positive IgG a nti

- HBc with negative HBsAg and negative

a nti

- HBs is of unclear clinical significance; the probability of HBV transmission to the uninfected recipient is likely low; and graft/patient survival post

- transplantation is unknown. Strategies to further minimize this risk should be considered (e.g., HBV vaccination of the transplant candidate if a nti

- HBs negativ e; hepatitis B immune globulin

, and anti

- viral therapy). (Category IIB) (Question 7)

7. F

. Testing with HBV NAT and ascertainment of IgM and IgG a nti

- HBc status should be
considered for total a nti

- HBc positive only donors to better evaluate the HBV risk in the recipient post

- transplantation. (Category IIB) (Question 7)

7. G

. Transplantation of an organ from an HCV

- infected donor into an HCV

- infected transplant candidate may be considered given that the risk

- benefit appears favorable, as patient and graft

su rvival appear to be similar to receiving an organ from an HCV

- uninfected donor. (Category IIB) (Question 7 )

7.H. Transplantation of an organ from an HCV

- infected donor into an HCV

- uninfected transplant candidate should not be performed unless the risk to the recipient of not performing the transplant* is elevated and deemed to be greater than the probability of HCV transmission and risk of disease development. ( Category IB) (Question 7) * L ife

- threatening illness requiring transplantation when no other orga ns are available and no other lifesaving therapies exist.

7.I. When organs from HCV

- infected donors are utilized, transplant centers should obtain
informed consent from the patient regarding the probability of HCV transmission and implement strategies to detect new infection quickly by post

- transplant recipient testing using HCV NAT at
minimum and also evaluat ing for the use of anti

- viral therapy. ( Category IB) (Question 7)

7. J . Since rates of infection transmission and recipient outcomes vary by organ, o rgan donor screening for deceased donors should still be done even if results cannot be obtained before the organ is transplanted , in order to guide recipient management post

- transplantation. Specifically, screening results for HIV, HBV or HCV may be reported following organ transplantation in
situations of life

- threatening illness where benefits of transplantation outweigh potential risks of
infection transmission

. (Category IB) (Question 7)

7. K . Research is needed concerning the risk

- benefit of transplanting organs from HIV

- infected
donors into HIV

- infected recipients, given the need for transplants in HIV

- infected recipients79

and improved o utcomes with the availability of highly active anti

- retroviral therapy (HAART). (No Recommendation/unresolved issue) (Question 7)

F igure 12

. Clinical Outcomes of Negative Recipients: Positive vs. Negative Donors, HBV and HCV, Kidney or Liver

Note : The diagonal line represents no difference in survival between those who received an organ from a positive donor and those wh o received an organ from a negative donor. Points above the diagonal line favor recipients of organs from positive donors, wher eas points below the diagonal line favor recipients of organs from negative donors. This figure only includes studies that reported graft or survival data as percentages, and it only includes the longest follow

- up timepoint from each study. The full data are p rovided in Table 68. None of the plotted studies reported confidence intervals. Studies with a lower case „s‟ next to the point reported that the compa rison of full survival curves was statistically significant; all other studies either did not report whether the difference w as statistically significant, or reported that the difference was not statistically significant. One of the studies did not report results on a percentage sca le, and so its results do not appear in the plot. This was the Abbott et al. (2003) 182

, 183 study, which found an adjusted hazard ratio of death of 2.25 (95% CI: 1.5 6 to 3.24) in favor of recipients of organs from HCV

- donors.80 Figure 13

. Clinical Outcomes of Positive Recipients: Positive vs. Negative Donors, HBV, Kidney or
Liver

Note : The diagonal line represents no difference in survival between those who received an organ from a positive donor and those who received an organ from a negative donor. Points above the diagonal line favor recipients of organs from positive donors, wher eas points below the diagonal line favor recipients of organs from negative d onors. This figure only includes studies that reported graft or survival data as percentages, and it only includes the longest follow

- up timepoint from each study. The full data are provided in Table 68 . None of the plotted studies reported confidence inte rvals. Studies with a lower case „s‟ next to the point reported that the comparison of full survival curves was statistically significant; all other studies either did not report whether the difference was statistical ly significant, or reported that the di fference was not statistically significant.81 Figure 1 4. Clinical Outcomes of Positive Recipients: Positive vs. Negative Donors, HCV, Kidney

Note : The diagonal line represents no difference in survival between those who received an organ from a positive donor and those who received an organ from a negative donor. Points above the diagonal line favor recipients of organs from positive donors, wher eas points below the diagonal line favor recipients of organs from negative d onors. This figure only includes studies that reported graft or survival data as percentages, and it only includes the longest follow

- up timepoint from each study. None of the plotted studies reported confidence intervals. Studies with a lower case „s‟ nex t to the point reported that the comparison of full survival curves was statistically significant; all other studies either did not report whether the difference was statistically significant, or reported that t he difference was not statistically significa nt. One of the studies did not report results on a percentage scale, and so its results do not appear in the plot. This was the Abbott et al. (2003) 182

, 183 study, which foun d an adjusted hazard ratio of death of 2.04 (95% CI: 1.20 to 3.45) in favor of recipie nts of negative organs.82 Figure 15. Clinical Outcomes of Positive Recipients: Positive vs. Negative Donors, HCV, Liver

Note : The diagonal line represents no difference in survival between those who received an organ from a positive donor and those wh o received an organ from a negative donor. Points above the diagonal line favor recipients of organs from positive donors, wher eas points below the diagonal line favor recipients of organs from negative donors. This figure only includes studies that reported graft or survival data as percentages, and it only includes the longest follow

- up timepoint from each study. The full data are provided in Table 68. None of the plotted studies reported confidence intervals around the data. Studies with a lower case „s‟ n ext to the point reported that the comparison of full survival curves was statistically significant; all other studies either did not report whether the differe nce was statistically significant, or reported that the difference was not statistically signifi cant. One of the studies did not report results on a percentage scale, and so its results do not appear in the plot. These was the Marroquin et al. (2001) 184 study, which found an adjusted

two

- year odds of graft failure of 0.88, in fa vor of recipients of positive organs, and an adjusted two

- year odds of patient death of 0.51, also in favor of recipients of positive organs.83 TOPIC V: POTENTIAL RISKS AND BENEFITS OF TRANSPLANTING, OR NOT TRANSPLANTING, ORGANS FROM DONORS WITH RISK FAC TORS FOR HIV, HBV, OR HCV (Questions 8,9,10)



### Question 8. How do the clinical outcomes of transplant recipients who receive organs from donors with behavioral or nonbehavioral risk factors compare to those who remain on the transplant list?

This question differs from Question 7 since the donor is not known to be infected, but is identified as having an increased probability of infection due to certain behavioral or nonbehavioral characteristics

. T wo simulation

s tudies met inclusion criteria

, 200

, 201 but made different comparisons and, therefore, were considered separately. Due to the paucity of evidence, we also looked for studies comparing the clinical outcomes of recipients of organs f rom IRDs to recipients of organs from standard donors. No such comparative studies were identified.

Q8. A. Estimated recipient outcomes after renal transplantation comparing “transplant” and “discard” policies There was very low quality evidence that exami ned clinical outcomes of transplant candidates receiving organs from donors with risk factors for HIV, HBV or HCV versus remaining on the transplant list. ( Table 76 ) The study applied a Markov process to address whether kidneys of deceased IRDs should be t ransplanted or
discarded. 200 Four types of IRDs were considered: intravenous drug user (IDU), men who have sex with men (MSM ), commercial sex workers ( CSW)

, and prison inmates (inmates). The main outcome measures were patient survival, quality

- adjusted life

- years (QALYs), number of organs transplanted and cost of care. Comparisons were made between patients on the waiting list who received kidneys from either standard criteria or IRD donors (transplant group) or from standard criteria donors only (discard group). Having a risk of HIV or HCV infection only was considered. Assumptions about the incidence and prevalence of these in fections within the general, potential donor and potential recipient populations are found in Tables 70 and 71 . Of note, estimated incidence and prevalence rates of HIV and HCV in the specific behavioral risk population were used as a proxy for potential d onors. Key assumptions about the donors, recipients, death rates, costs and quality

- of

adjusted life years that were applied in the model are found in Table 69 . The base case simulation assumed that IRD donors were current IDUs with negative immunoassay a nd NAT screening results for HIV and HCV. The “transplant” strategy resulted in lower mortality, more QALYs, lower cost, and slightly more HIV infections. ( Table 72 ) For this case, more HCV infections occurred with the “discard” strategy. This strategy led to more time on hemodialysis with an assumption that the incidence of HCV is significantly higher when on dialysis than after kidney transplant. Separate analyses were performed for the three other types of IRDs (MSM, CSW, prison inmates) with results ver y similar to the base case for outcomes. ( Table 73 ) Results of numerous one

- way sensitivity analyses found that in most cases the conclusions of the base case “were not substantially changed,” except that HCV infections were strongly influenced by assumpti ons about incidence rates. Authors concluded that “the „Discard‟ policy would yield fewer HCV infections only in a setting where a recipient‟s risk of infection on dialysis is very low, while the probability of CDC

- IRD infection in a donor is high.” 200

Q8 .B. Estimated mortality from receiving a kidney from an at

- risk donor versus one

- year waitlist mor t alities There was very low quality evidence that examined clinical outcomes of transplant candidates receiving organs from donors with risk factors for HIV, HBV or HCV versus remaining on the transplant list. ( Table 76 ) This study was a comprehensive risk analysis of considerati ons pertaining to solid organ donation. 201 The study emphasized that the risk of recipient death from a donor infection is only one among a set of competing risks, including the risk of dying while on the waitlist, the risk of dying after the transplant (regardless of the donor‟s status), and risks of dying from medications, employment, transportation, and recreation. Much of the data reported in the article was not relevant to the research question; therefore we were selective in the data reported
here. One

- year waitlist mortality estimates for a standard criteria donor were based on a Markov model that84 utilized 90

- day waitlist mortality and transplantation probabilities from the OPTN/SRTR 2007 Annual Report. Mortality rates were repo rted separately for 12 different types of recipients

. ( Table 74 ) For at

- risk donors, the study only addressed HIV. When considering disease transmission to a recipient, an infectious risk of 46 per 100,000 for HIV was provided based on OPTN high

- risk donor data. In a conservative analysis, the authors assumed that HIV is 100% fatal, which corresponds to a 0.046%, mortality rate. This estimate is much lower
than all of the one

- year waitlist mortality rates ranging from 2.7% to 21.8%

. ( Table 74 ) They conclude d that the waitlist mortality risk far outweighs the risk of HIV

- related mortality associated with receiving an organ from a serologically negative donor with a behavioral risk factor. They did not attempt to make mortality estimates for
either HBV or HCV due to insufficient documentation in the literature.



### Question 9. What is the impact of excluding potential solid organ donors with behavioral or nonbehavioral risk factors on the organ donor pool?

Q9.A. There was very low quality evidence estimating the number of donors that would be excluded from organ recovery based on having risk factors for HIV, HBV or HCV. ( Table 76 ) One study included for this question was described in detail under Question 8

. 200 Over a 20

- year period, the study estimated there would be a 25.3% reduction (250 fewer kidneys per 1,000 patients available for transplantation) if IRDs were excluded . The study only considered HIV and HCV and four types of behavioral exclusions (IDU, MSM, CSW, and prison inmates )

. Exclusions for other reasons (e.g., HBV risk, or nonbehavioral risk factors for HIV or HCV) would likely result
in a larger reduction in the organ don or pool.



### Question 10. What is the impact of false positive tests on the organ donor pool?

10.A. Our search did not identify any studies that estimated the number of donors or organs excluded from recovery due to false positive results for HIV, HBV, or HCV.

Questions 8, 9, and 10 Recommendations

8/9. Further research is needed to evaluate transplant candidate and recipient outcomes if organ donors with behavioral or nonbehavioral risk factors were excluded from donating. This process may also require c omparing incidence of infection among population subsets within risk factors. (No recommendation/unresolved issue) (Category 8/ 9)

10. Research is needed to evaluate the rate of false positive immunoassay and NAT results for HIV, HBV and HCV among potential organ donors and the percentage of cases where donors are declined by organ type. (No recommendation/unresolved issue) (Category 10)85 TOPIC VI: APPROACHES AS TO HOW RECIPIENTS CAN BE INFORMED ABOUT THE RISK OF HIV, HBV AND HCV TRANSMISSION AND BE EVA LUATED FOR POSSIBLE EXPOSURE POST

TRANSPLANTATION (Expert Opinions 1, 2, and 3)

Expert Opinion 1 (E O

. 1 .): How and when should informed consent be obtained from potential recipients

to help them consider the risks of d onor

- derived HIV, HBV, and HCV?

Background and Justification

Organ t ransplantation always carr ies a risk of donor

- derived disease transmission. 202

, 203 Thus, donors
without identified risk factors are not presumed to be risk

- free, but rather are differentiated from donors
with risk factors in that the former possess no known serological or historical characteristics that indicate
elevated risk. D ue to the scarcity of transplantable organs and that the loss of donated organs results in increased mortality of patients remaining on the transplant waitlist, d onors with increased risk for infections are not barred from contributing to the organ supply, as they generally are from contributing to the blood or tissue supply . They are instea d evaluated on a case by case basis by transplant centers weighing risks/benefits for each individual transplant candidate

. Informed consent is an important part of this process. Current recommendations for obtaining informed consent from a potential recip ient include the OPTN policy and recommendations from the 2009 consensus conference on NAT screening of potential donors.

The 1994 PHS exclusionary criteria for HIV have been used to assess risk for HIV, HBV, and HCV in potential donors. OPTN polic y requi re s that the host OPO communicat e to transplant centers information of donors meeting any of these criteria which it further defines as a “high risk”. 18 Transplant centers must then inform the potential recipie nt of this information and maintain documentation of informed consent. If a potential recipient is unable to provide informed consent, the legal next of kin or other appropriate surrogate is required to do so. However, there is currently no uniform consent process resulting in variability among transplant centers.

The 2009 consensus conference on NAT screening of potential donors, therefore, recommended establishing uniform consent standards across transplant centers, and made recommendations as to what

s pecifics should be addressed at the time of listing and at the time of an organ offer. 28 At the time of listing, they recommended discussing the following with potential recipients: that although tran splantation carries the risk for potentially donor

- derived transmission of infection, not performing the transplant often carries a higher risk of death than the risk attributable to donor

- transmitted infection; relaying the risks of donor
transmission of infections including HIV, HBV, and HCV; the limitations of available testing and the potential for both false

- positive and false

- negative test results; relaying the risk of transmission of infections placed in the broader context of risk including risks as sociated with the use of extended

- criteria donors as well as everyday occurrences to make their magnitude understandable to the potential recipient; and that risk assessment using donor histories may be limited by the knowledge of the person providing the
information. At the time of an organ offer, they recommended disclosing specific donor history and testing results to enable the potential recipient to understand the risk while protecting donor identity and emphasizing that the transplant team has assesse d the risk of the donor with the risk of not performing the transplant.

Informed consent at the time of an organ offer has been controversial with s ome experts concerned that patients may be less able to rationally weigh the risks of accepting or declini ng a particular organ at the time an organ is offered (i.e., choices made in such hurried circumstances do not reflect patients‟ underlying
values or well

- considered preferences ). 204

, 205 Alternatively, others have advocated for obtaining specific86 informed consent and providing full disclosure of the donors‟ risk behaviors to patients at the time of the organ offer to allow patients to make an informed decision based on the donor‟s specifi c characteristics

. 206 Obtaining specific informed consent on multiple occasions would help to reinforce patient understanding of complex risk information critical to this decision, and to promote an informed treatment dec ision.

Expert Opinion 2 (EO.2.): When should testing of a transplant recipient be done to detect HIV, HBV, and
HCV transmission from the donor?

Background and Justification

Unexpected transmission of donor

- derived disease to uninfected organ transplant recipients appears to be

rare. 17 The exact incidence of disease transmission is unknown because disease transmission is not actively or uniformly assessed across transplant centers in the United States; this is particularly true for bloodborne viruses, such as HIV, HBV, and HCV. 27 Furthermore, the OPTN does not have formal policies requiring
post

- transplant assessment of recipients, and therefore, does not collect results of the testing when performed.

There are two major goals in recommending testin g of transplant recipients:

1. To identify donor

- derived disease transmission and implement interventions (i.e. antiviral therapy) early post

- transplant to try and minimize the impact of the disease on the recipient.
2. To provide insight into the true incidenc e of donor

- derived disease transmission.

As such, testing needs to be conducted to allow recognition of infection early enough to permit timely intervention while at the same time providing sufficient follow

- up to prevent missing disease transmission.
Th ere are currently several guidelines that provide a template for timing and frequency of screening individuals exposed, through occupational and non

- occupational means, to HIV, HBV, and HCV. 207

- 210 Because HIV, HBV, and/or HCV exposure via organ transplantation may be associated with a larger amount of virus transmission compared t o occupational or non

- occupational exposures and more rapid progression of disease secondary to the use of immunosuppressive medications, a modified recipient testing schedule of 1, 3 and 12 months post

- transplant has been recommended by a 2009 consensus c onference on NAT testing of potential donors. 28

, 211 Sero

- conversion of transplant recipients may be impeded by the immunosuppressive medications the patients receive. 8

, 17

, 212 I n most cases of known donor

- derived HCV transmission, recipients failed to seroconvert to HCV seropositive status despite having high viral titers by
NAT. 17

, 211

, 212 Likewise, in the confirmed HIV/HCV donor

- derived transmission, 1 of 4 patients had an
indeterminate western blot. 212 As such, any post

- transplan t testing of recipients should include direct
measure of the virus itself through antigen detection (i.e. HBsAg for HBV) or NAT (i.e., HIV and HCV). Recipient baseline testing, done at the time the recipient is admitted for transplantation but before placement of the organ, should also be done to rule

- out pre

- existing disease prior to transplantation.87 Expert Opinion 3 (E O

. 3 .): How should donor and recipient specimens be collect ed and stored for potential i nvestigation of donor

- derived HIV, HBV, and HCV infection ?

Background and Justification

The availability of both donor and recipient archived blood specimens are critical for investigations to determine if a recipient infected with HIV, HBV or HCV is donor

- derived. Appropriate specimen collection, labeling, transportation, handling and storage facilitate the accuracy of reported results for serologic and NAT screening

. Collection of two separ ate archival samples ( from all donors and those recipients who receive organs from donors at increased risk for HIV, HBV, or HCV) for immunoassay and
NAT reduces the possibility of specimen cross contamination or deterioration of nucleic acids through

spec imen handling and storage

. L abel ing each specimen with a minimum of two unique identifiers ensures a confidential and unbroken chain of traceability to the identity of the donor and recipient.

Viral nucleic acid may deteriorate over time depending on stor age conditions . For example, r epeated freeze

thaw cycles can cause a moderate reduction in viral nucleic acid levels. 213

- 215 Procedures to maximize sample quality include sepa rating samples that might be used for NAT into multiple aliquots prior to long term storage with storage temperature maintained at

- 70 o C. Furthermore, avoid ing temperature extremes when archived samples are shipped for testing inhibits s pecimen hemolysis

, which can result in both false positive serologic results a nd false negative NAT results. 216 Therefore

, transport ing archived samples to a testing laboratory on dry ice is a common practice, as well as documenting t he sample quality and
condition

, with respect to both temperature and hemolysis

, on receipt in the testing laboratory. OPTN policy requires donor blood samples be retained for a minimum of 10 years after transplant. 18

Massive blood loss and intravascular volume replacement by transfusion of crystalloid and colloid solution and blood products can cause hemodilution and result in unreliable test results for transmissible
infections. 3

, 217 If significant hemodilution , defined as ”a sample with plasma dilution sufficient to affect the results of communicable disease testing utilizing an FDA

- approved hemo dilution calculation,” is confirmed, the tests that used hemodiluted samples and the hemodilution calculation used are to be reported to the accepting transplant programs. 18 Calculations of dilution effects sho uld take into account blood products and colloid administered. It should also be noted that h emodilution calculation algorithms are not standardized and the limits of “acceptable” hemodilution have not been validated across all current versions of serologi c tests. 218 The impact and limits of hemodilutio n on NAT have not been extensively studied but, from a theoretical perspective based on viral loads documented in acutely infected blood donors and the results of minipool testing in blood donors, may have a significantly greater impact on the detection of some pathogens ( e.g., HBV) 219

, 220 compared to others ( e,g., HCV , HIV). 19

, 20

Administration of blood products (plasma, red blood cells, platelets) and intravenous or intramuscular immunoglobulin may result in the transfer of passive antibody and result in false positive test results. 221 Although blood products are universally screened

, many of the infectious disease markers of concern , for organ donors and recipients who receive blood product, are significantly more likely to have false positive
results for hig hly prevalent analytes that do not preclude blood donation ( e.g., anti

- HBs ) but are important as part of the pre

- transplant donor or recipient screen. Receipt of blood and immunoglobulin products by donors and recipients in the three months prior to screen ing should be recorded, if known. Passive maternal antibody may also be detectable in children less than 18 months of age; serostatus and infection status may
be difficult to resolve. R ecent HBV immunization may also result in false positive HBsAg testing results as HBsAg reactivity has been found in individual up to 5 days after (HBV) immunization. 222 When screening is urgent, efforts should be made to retrieve available pre

- transfusion samples on the donor and recipients as88 close as possible to the time of transplant.

Expert Opinions 1, 2, and 3 Recommendations

EO1.A. A shared decision

- making process between the prospective recipient and the listing clinician
should start at the time that the patient is placed on the transplant waitlist . Patients should be counseled to consider all potential risks of both accept ing and rejecting specific types of organs from donors known to be infected with HBV or HCV; or donors at increased risk for HBV, HCV, or HIV infection . (Category

I B ) (Expert Opinion 1 )

EO1. B

. Further research is needed t o reduce the chance that decisions would be biased against specific
donor risk behaviors . Consider development and evaluation of a relative or comparative risk

- based quantitative process, such as a donor risk index, to allow a patient to accept or reject a donor based on
level of risk for transmitting HIV, HBV, or HCV. (No recommendation/unresolved issue) (Expert Opinion 1)

EO1. C . Patients should be allowed opportunities to discuss with clinicians issues related to organ and associated risk acceptance at any time while on the waiting list. ( Category I B ) (Expert Opinion 1 )

E01.D. At the time of the organ offer, the transplant center team primarily responsible for the patient‟s
care should have a discussion with the prospective recipient that includes more specific information regarding the probability that this specific donor may transmit HIV, HBV, or HCV based on the donor history and blood test results available at that time to enable the potential recipient to und erstand the risk. Since vessel conduits may be transplanted from a different organ donor than the primary organ transplant, with different associated donor risks, an additional informed consent discussion by the transplant center team may need to take place separately for the vessel conduit. (Category I B (Expert Opinion 1 )

EO1. E . Transplant candidates should be informed that although all donors are screened for HIV, HBV, and HCV, there are limits to screening and no screening question or laboratory tes t can completely eliminate the risk for transmitting these infections. (Category I B ) (Expert Opinion 1 )

EO2.A. Transplant candidates , for whom follow

- up testing is planned post

- transplant, should have a serologic assessment of their HIV, HBV, and HCV stat us at the time that they are admitted to the hospital to undergo the organ transplant but prior to implantation of the organ. (Category I B ) (Expert Opinion 2 )

EO2.B. Post

- transplant testing should be done for HIV, HBV, and HCV, unless infection has been
d ocumented pre

- transplant, for all recipients of organs from living or deceased donors specifically when 1) recognized risk factors place them at increased probability of acquiring donor

- derived HIV, HBV or HCV; 2) the donor screening specimens are hemodil uted; 3) a donor medical or social history is unavailable; or 4) the donor screening assay is repeatedly reactive. (Category I B ) (Expert Opinion 2 )

EO2.C. Where the donor (living or deceased) was infected with HBV or HCV, post

- transplant recipient testing should be done, unless recipient infection has been documented pre

- transplant. (Category I B ) (Expert Opinion 2 )89 EO2.D. Recipient testing should be conducted for HBV, with respect to Expert Opinion 2B and 2C recommendations, at a minimum of 3 times at int ervals of 1, 3 and 12 months post

- transplant and include screening for a nti

- HBs

, a nti

- HBc , and HBsAg (unless known through prior testing to be infected pre

transplant). (Category I B ) (Expert Opinion 2 )

EO2.E. Recipient testing should be conducted for HIV with respect to Expert Opinion 2B and 2C recommendations, at a minimum of 2 times at intervals of 1 and 3 months post

- transplant and include

HIV

- 1 and 2 antibody and HIV NAT or testing of equivalent sens itivity (unless known through prior testing to be infected pre

- transplant). NAT or testing of equivalent sensitivity is important for HIV detection as infected recipients may remain seronegative due to immunosuppression. (Category I B ) (Expert Opinion 2 )

E O2.F. Recipient testing should be conducted for HCV with respect to Expert Opinion 2B and 2C recommendations, at a minimum of 2 times at intervals of 1 and 3 months post

- transplant and include HCV antibody and HCV NAT or testing of equivalent sensitivity ( unless known through prior testing to be infected pre

- transplant). NAT or testing of equivalent sensitivity is important for HCV detection as infected recipients may remain seronegative due to immunosuppression. (Category I B ) (Expert Opinion
2 )

EO2.G. Dat a on the results of pre

- and post

- transplant bloodborne pathogen infection assessments in recipients should be collected nationally and analyzed on a regular basis to inform policy decisions and future screening recommendations. Nationally aggregated data on donor

- derived infections should be disseminated to allow the transplant community to have access to the data. (Category I B ) (Expert Opinion 2 )

EO2.H. Any documentation of new infection in a recipient must be reported to the OPTN as required by policy a nd to appropriate local and state health departments as required by local and state law. (Category IC) (Expert Opinion 2 )

EO3.A. For archival blood specimens

, consider collecting two separate samples from all donors (living and deceased) and those recipients who receive organs from donors at increased risk for HIV, HBV, or
HCV to reduce the possibility of specimen cross

- contamination . Ideally, one sample from each individual of 10 ml in a serum separator tube would be collected and processed to create 5 ml aliquots of serum for serologic testing. A second plasma sample of 3

- 5 ml collected in EDTA would be processed to create 1 ml aliquots for NAT screening

. S maller samples wo uld be collected from pediatric donors and from pediatric recipients prior to implantation of the organ. Samples should be stored for at least 10 years. (If only one specimen tube is feasible, all FDA licensed

- screening tests and/or FDA

- approved tests are for
use with serum or plasma specimens.) (Category II B ) (Expert Opinion 3 )

EO3.B. For initial deceased donor screening

, consider collect ing a separate ethylenediaminetetraacetic acid (EDTA) plasma specimens for NAT rather than using s erum samples for sero logic assays. When an alternate specimen is not available and a previously assayed serum is used for NAT, documentation should be provided. (If only one specimen tube is feasible, all FDA licensed

- s creening tests and/or FDA approved tests are for with of s erum or EDTA plasma specimens.) (Category II B ) (Expert Opinion 3 )

EO3.C. When storage capacity exists and specimen volume permits, separating EDTA plasma samples that might be used for future NAT into multiple aliquots should be considered prior to long term storage90 as repeated freeze

- thaw cycles can cause moderate reduction in viral nucleic acid levels , with plasma samples maintained at approximately minus 70 o C. (Category II B ) (Expert Opinion 3 )

EO3.D. Massive blood loss and intravascular volume replace ment by infusion of crystalloid and colloid solution and transfusion of blood products can cause plasma dilution and result in unreliable test results
for transmissible infections. Donors should be considered at increased risk for harboring HIV, HBV and
HC V when donor samples are determined to be diluted by an accepted plasma dilution algorithm and calculation method, such as provided by FDA, 13 designed to evaluate volumes adm inistered in the 48 hours before specimen collection, even when no risk factors are identified. (Categ o ry I B ) (Expert Opinion 3 )

EO3.E. Further research is needed to identify the limits of acceptable plasma dilution. Plasma dilution algorithms and calculation methods are not standardized for organ donors and the limits of acceptable plasma dilution have not been validated across HIV , HBV and HCV serological assays used for organ
donors. (No recommendation/unresolved issue) (Expert Opinion 3 )91 

# VIII

. APPENDICES



# G UIDELINE FOR REDUCING TRANSMISSION OF HUMA N

IMMUNODEFICIENCY VIR US 

# ( HIV 

# ), HEPATITIS B VIRUS 

# ( HBV 

# ), AND

HEPATITIS C VIRUS 

# ( HCV 

# ) THROUGH SOLID ORGAN

TRANSPLANTATION92



### APPENDIX : TABLE OF CONTENTS

Appendix 1

– Factors identified in the literature to be associated with increased likelihood of recent HIV, HBV or HCV

Infection

................................ ................................ ................................ ................................ ................................ ............... 94

Appendix 2

– GRADE Tables (Organized by Key Question)

Key Question 1 : What are the prevalence and incidence rates of HIV, HBV, and HCV among potential solid organ donors?

GRADE Table

................................ ................................ ................................ ................................ ................................ ...................... 99

Key Question 2: What behavioral risk factors are associated with an increased probability of infection with HIV, HBV, or

HCV? What is the prevalence of these factors among potential solid organ donors?

GRADE Table

................................ ................................ ................................ ................................ ................................ .................... 103

Key Question 3: What behavioral risk factors are associate d with an increased probability of infection with HIV, HBV, or

HCV? What is the prevalence of these factors among potential solid organ donors?

GRADE Table

................................ ................................ ................................ ................................ ................................ .................... 109

Key Question 4: What nonbehavioral factors are associated with an increased probability of infe ction with HIV, HBV, or

HCV? What is the prevalence of these factors among potential solid organ donors?

GRADE Table

................................ ................................ ................................ ................................ ................................ .................... 112

Key Question 5: What are the test characteristics of the screening methods available to detect HIV, HBV, and HCV in

potential solid or gan donors? Do test characteristics differ in particular populations and with donor clinical status (i.e., heart

beating vs. non

- heart beating donors OR adult vs. pediatric donors)?

GRADE Table

................................ ................................ ................................ ................................ ................................ .................... 127

Key Question 6: Which donor interventions reduce the prob ability of pathogen transmission from an organ donor infected with

HIV, HBV, or HCV to a previously uninfected recipient? ?

GRADE Table

................................ ................................ ................................ ................................ ................................ .................... 13893

Key Question 7: How do the clinical outcomes of recipients of organs from donors infected with HIV, HBV, or HCV comp are
to those who remain on the transplant list?

GRADE Table

................................ ................................ ................................ ................................ ................................ .................... 139

Key Question 8: How do the clinical outcomes of transplant recipients who receive organs from donors with behavioral or

nonbehavioral risk factors compare to those who remain on the transplant list?

GRADE Table

................................ ................................ ................................ ................................ ................................ .................... 143

Key Question 9: What is the impact of excluding potential solid organ donors with behavioral or nonbehavioral risk factors on

the organ donor pool?

................................ ................................ ................................ ................................ ................................ .............. 145

Key Question 10: What is the impact of false positive tests on the org an donor pool?

................................ ................................ .......... 14594



### Appendix 1 : Risk Factors

Given the paucity of literature identifying risk factors for incident infection, the potential risk factors identified from t he evidence in
the literature review in Table 9 of this document were reviewed with s ubjects matter experts on HIV and hepatitis to create a revised list of risk factors that would facilitate screening out incident (recent) HIV, HBV, or HCV infections in potential organ donors. The following risk factors associated with HIV, HBV and HCV in fection supplant the identified factors from the evidence review listed in
Table 9

. Each factor reflects an increased risk of infection due to HIV, HBV and/or HCV as there may be overlap between pathogen risks for each listed factor; unless otherwise speci fied, a particular factor does not convey risk due to only one pathogen or to all pathogens equally.

Donors who have engaged in the behaviors listed below are identified as being at increased risk . The revised list takes into consideration that 1) certain risk factors are probably markers for other factors identified in the systematic review and 2) scientific evidence associating certain factors with the bloodborne pathogens exists, but may not have met the inclusion criteria of the systematic
review or st udies were of insufficient quality to draw conclusions.

Table 3

. Factors identified in the literature to be associated with increased likelihood of recent HIV, HBV or HCV
Infection

● Sexual contact

■ Persons who have had sex with ≥2 partners in the preceding 12 months

■ Persons who have had sex with a person known or suspected to have HIV, HBV or HCV infection in the preceding 12 months

■ Men who have had sex with another man (MSM) in the preceding 12 months

■ Women who have had sex with a man with a history of MSM behavior in the preceding 12 months

■ Persons who have had sex in exchange for money or drugs in the preceding 12 months

■ Persons who have had sex with a person who had sex in exchange for money or drugs in the preceding 12 months

■ Persons who h ave had sex with a person who injected drugs by intravenous, intramuscular, or subcutaneous route
for non

- medical reasons in the preceding 12 months

● Birth to a mother infected with HIV, HBV or HCV (for infants ≤2 years of age)

● Persons who have injected dru gs by intravenous, intramuscular, or subcutaneous route for non

- medical reasons in the preceding 12 months

● Intra

- nasal use of an illicit drug (e.g., cocaine, heroin) in the preceding 12 months

● Inmate of a correctional facility (e.g., jail, prison, juvenil e detention) >3 consecutive days in the preceding 12 months

● Persons who have, or have been treated for, syphilis, gonorrhea, or genital ulcers in the preceding 12 months

● Persons who have been on hemodialysis in the preceding 12 months (for HCV only)95

● Person s who have immigrated to the United States in the preceding 12 months from a country of intermediate or high hepatitis B prevalence (for HBV only)

Sexual Contact

Persons who have had sex with ≥2 partners in the preceding 12 months

● HIV: R eview of the available studies reveals low quality evidence to suggest an association between having multiple sex partners and being at increased risk of HIV.

● HBV: Review of the outlined studies demonstrated moderate quality evidence to support having mu ltiple sex partners as risk
factor for HBV infection.

● HCV: Review of the outlined studies found moderate quality evidence confirming an association between HCV infection and having multiple sex partners

. Persons who have had sex with a person known or s uspected to have HIV, HBV or HCV in the preceding 12 months

● HIV : There was low quality evidence associating having sex with someone who is HIV

- positive and having HIV.

● HBV : There was very low quality evidence to support having a sex partner with a known HBV infection as a risk factor for HBV.

● HCV : We found low quality evidence to support having sex with people known to be HCV infected as a risk factor for HCV
infection.
Men who have had sex with another man (MSM) in the preceding 12 months

● HIV : There was moderate quality evidence identifying MSM as a risk factor for HIV.

● HBV : The review demonstrated moderate quality evidence to support an association between MSM behavior and HBV.

● HCV : There was very low quality e vidence to support MSM behavior as a risk factor for HCV infection. Females who have had sex with a male with a history of MSM behavior in the preceding 12 months

● Our search did not identify studies that examined the association between females who had sex with an ID with a male with a history of MSM behavior and acquiring HIV, HBV, or HCV Persons who have had sex with a person who injected drugs by intravenous, intramuscular, or subcutaneous route for non

medical reasons

● HIV: Our search did not identify studies that examine the association between sex with an IDU and acquiring HIV.

● HBV : Review of the available studies revealed very low quality evidence supporting an association between HBV infection and having sex with an injection drug user.

● HCV : Review of the outlined studies found moderate quality evidence supporting having sex with an IDU as a risk factor for
HCV. Persons who have had sex in exchange for money or drugs in the preceding 12 months

● HIV: A single study found very low quality evide nce which did not find an association between sex workers and HIV.

● HBV: We found very low quality evidence relating sex work and HBV infection.96

● HCV: We found low quality evidence to suggest an association between sex work and HCV.
Persons who have had sex with a person who had sex in exchange for money or drugs

● HIV: No studies were identified that looked at the association between HIV and sex with a sex worker.

● HBV : A single study of psychiatric inpatient veterans found very low quality evidence wh ich did not find an association between HBV and having sex with a sex worker in univariate analysis.

● HCV : We found very low quality evidence to suggest an association between having sex with a sex worker and having HCV. Persons who have had sex with a p erson who injected drugs by intravenous, intramuscular, or subcutaneous route for non

medical reasons in the preceding 12 months

● HIV : Our search did not identify studies that examined the association between sex with an IDU and acquiring HIV.

● HBV : Review of the available studies revealed very low quality evidence supporting an association between HBV infection and having sex with an injection drug user.

● HCV : Review of the outlined studies found moderate quality evidence supporting having sex with an IDU as a risk factor for
HCV.

Birth to a mother infected with HIV, HBV or HCV (for infants ≤2 years of age)

● HIV : Our search did not identify studies on behavioral risk factors in children, or on the risk of infection from mothers who engage in those risk behaviors.

● HBV : Our search did not identify studies on behavioral risk factors in children, or on the risk of in fection from mothers who engage in those risk behaviors.

● HCV : Our search did not identify studies on behavioral risk factors in children, or on the risk of infection from mothers who engage in those risk behaviors.

Persons who have injected drugs by in travenous, intramuscular, or subcutaneous route for non

- medical reasons in the preceding 12 months

● HIV : We found low quality evidence suggesting an association between IDU and HIV.

● HBV : There was low quality evidence to support IDU as a risk factor for HBV infection.

● HCV : This review demonstrated moderate quality evidence to support IDU as a risk factor for HCV.

Intra

- nasal use of an illicit drug (e.g., cocaine, heroin) in the precedi ng 12 months

● HIV : We found low quality evidence associating use of cocaine or street drugs and HIV infection.

● HBV : There was very low quality evidence associating non

- injection illicit drug use with HBV.97

● HCV : There was low quality evidence associating HCV with non

- injection drug use.

Inmate of a correctional facility (e.g., jail, prison, juvenile detention) > 3 consecutive days in the preceding 12 months

● HIV : A single study found very low quality evidence t o suggest an association between being incarcerated and having HIV.

● HBV : We found very low quality evidence to suggest an association between being incarcerated and having HBV.

● HCV : We found low quality evidence to support incarceration as a risk facto r for HCV.

Persons who have, or have been treated for, syphilis, gonorrhea, or genital ulcers in the preceding 12 months

● HIV : This review found low quality evidence associating HIV with having another infection (STD).

● HBV : We found low quality evidence to suggest an association between having HBV and exposure to, or having, other types of infection (STDs).

● HCV : We found low quality evidence to suggest an association between STD or other infections and having HCV.

Persons who have been on hemodialysis in the preceding 12 months (for HCV only)

● HCV : Hemodialysis: There was low quality evidence which found an association between hemodialysis and HCV.

Persons who have immigrated to the U.S. in the preceding 12 months from a country of intermediate or high prevalence (for HBV only)

● HBV : This review found very low quality evidence to suggest a relationship between HBV and an individual‟s race, ethnicity or national origin. Grade of evidence specifically for national origin /birthplace was also rated very low.

The prevalence of chronic HBV infection is intermediate (≥2%) or high (≥8%) in the following geographic regions. These countries may be updated periodically as new information becomes available : 1) A frica: all countries ; 2) Asia (comprising Southeast Asia, East Asia, and Northern Asia): all countries ; 3) South and Western Pacific islands, except Australia and New Zealand ; 4) Middle East, except Cyprus ; 5) Eastern Europe, except Hungary ; 6) Western Europe: Spai n, Portugal and Greenland ; 7) South America: Brazil, Ecuador, Guyana, Venezuela, French Guyana, Peru and Suriname, and Amazonian areas of northern Bolivia and southern Columbia; 8) Central America: Honduras, and Guatemala ; 9) c ertain parts of the Caribb ea n: Haiti, Dominican Republic; 10) Alaska Natives and indigenous populations in Northern Canada98

Prevalence of Hepatitis B Surface Antigen, 2010

Source: Centers for Disease Control and Prevention. CDC Health Information for International Travel 2010. Atlanta: U.S. Department of Health and Human Services, Public Health Service, 2009

http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter

- 2/hepatitis

- b.aspx99 

### APPENDIX 2: GRADE TABLES

Question 1: What are the prevalence and incidence rates of HIV, HBV, and HCV among potential solid organ
donors?

Table 1. GRADE Table for Question 1 (Epidemiology)

Pathogen

Outcome Quantity and

Type of Evidence Findings Star ting Grade Decrease GRADE Increase GRADE

GRADE of

Evidence for

Outcome Overall

GRADE of

Evidence

Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Confounders would reduce the effect

HIV Incidence 1 study of potential

tissue donors 45
1 study of the U.S. general population 46

, 47 In the study of potential tissue

donors, incidence of 30.11 per 100,000 person

- years In the general population study, incidence of 56,300 in 2006, which corresponds to 18.8 per 100,000 person years Hig h 0

- 1

- 1 0 0 0 0 0 Low100 Pathogen

Outcome Quantity and Type of Evidence Findings Star ting Grade Decrease GRADE Increase GRADE

GRADE of

Evidence for

Outcome Overall

GRADE of

Evidence

Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Confounders would reduce the effect

Prevalence 2 studies of potential

organ donors 34

, 36
1 study of potential
tissue donors 45
1 study of the U.S. general population 52 In the studies of tested

potential organ donors, prevalence of HIV was
0/22 (0%), and prevalence of HIV or syphilis was and 2/94 (2.1% or 1 in 48).
In the study of potential tissue donors, prevalence was 10/10,910 (0.093% or
1 in 1,090).

In the general population study, prevalence was 1,106,400 in 2006 (0.37%, or
1 in 270) High 0

- 1

- 1 0 0 0 0 0 Low Low

HBV Incidence 1 study of potential

tissue donors 45
1 study of the U.S. general population 48

, 49 In the study of potential tissue

donors, incidence of 18.325 per 100,000 person

- years In the general population study, 43,000 incidence in 2007, which corresponds to 14.4 per 100,000 person

- years High 0 0

- 1 0 0 0 0 0 Moderate101 Pathogen

Outcome Quantity and Type of Evidence Findings Star ting Grade Decrease GRADE Increase GRADE

GRADE of

Evidence for

Outcome Overall

GRADE of

Evidence

Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Confounders would reduce the effect

Prevalence 1 study of HBV in

potential organ donors 35

2 studies of hepatitis(including HBV and HCV) in tested potential organ
donors 34

, 36
1 study of potential
tissue donors 45
1 study of the U.S

. general population 50 In the study of HBV in potential

organ donors, prevalence was 22/446 (4.9%, or 1 in 20).

In the two studies of hepatitis in potential organ donors, prevalence of 5/94 (5.3%, or 1 in 19) and4/22 (18.2%, or 1 in 6).
The study of potential tissue donors reported a prevalence of 25/10901 (0.229%, or 1 in 436)..

In the general population study, prevalence of chronic
infection was 1.1 million in 2006 (0.36% or 1 in 274) High 0

- 1

- 1 0 0 0 0 0 Low Low

HCV Incidence 1 study of potential

tissue donors 45
1 study of the U.S. general population 48

, 49 In the study of potential tiss ue

donors, incidence of 12.38 per 100,000 person

- years In the general population study, 17,000 incidence in 2007, which corresponds to 5.7 per 100,000 person

- years High 0

- 1

- 1 0 0 0 0 0 Low102 Pathogen

Outcome Quantity and Type of Evidence Findings Star ting Grade Decrease GRADE Increase GRADE

GRADE of

Evidence for

Outcome Overall

GRADE of

Evidence

Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Confounders would reduce the effect

Prevalence 1 study of HCV in

potential organ donors 33
1 study of “hepatitis” in potential organ donors 34

4 studies of prevalence

among pre

- 1991 organ
donors 37

- 44
1 study of potential
tissue donors 45
1 study of the U.S. general population 51 In the study of HCV in potential

organ donors, prevalence was 2/55 (3.6%, or 1 in 28).
In the study of HBV and HCV in potential organ donors, prevalence was 5/430 (1.2%, or 1 in 86)

In the studies of pre

- 1991 organ donors, combined estimate of prevalence of 4.0%
or 1 in 25.
In the study of potential tissue donors, prevalence of 119/10915 (1.091%, or 1 in 92).

In the general population study, prevalence of chronic
infection was 3.3 million in
1999

- 2002 (1.1 % or 1 in 86) High 0

- 1

- 1 0 0 0 0 0 Low Low103 

### Question 2 : What are the rates of transmission to recipients from donors infected with HIV, HBV, or HCV? Do the rates vary by the organ transplanted or when the donor was infected?

Table 2. GRADE Table for Question 2 (Transmission )

Definitions
of Donor Positivity Recipient

tested for: Quantity

and Type of
Evidence Range of

Results

Starting Grade Decrease GRADE Increase GRADE

GRADE
of
Evidence
for
Outcome Overall

GRADE
of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Confounders would reduce the effect

HBV and Liver T ransplantation

Anti

- HBc+ HBsAg 5 OBS 56

- 63 0% to 94% High

- 1

- 1 0 0 0 0 0 0 Low

Low Anti

- HBc+ HBeAg 2 OBS 59

- 63 40% to 94% High

- 2

- 1 0 0 0 0 0 0 Very Low

Anti

- HBc+ anti

- HBc 2 OBS 56

, 57 0% to 78% High

- 1

- 1 0 0 0 0 0 0 Low

Anti

- HBc+ serum HBV

DNA 2 OBS 59

- 63 4 0% to 94% High

- 1

- 1 0 0 0 0 0 0 Low

Anti

- HBc+ “Developed

de novo infection” 1 OBS 64 6% High

- 2

- 1 0 0 0 0 0 0 Very Low

Anti

- HBc+ anti

- HBs 2 OBS 56

, 57 0% to 44% High

- 1

- 1 0 0 0 0 0 0 Low

Anti

- HBc+ and HBsAg

HBsAg 9 OBS 54

, 55

, 65

-

72 0% to 78% High

- 2

- 1 0 0 0 0 0 0 Very Low

Anti

- HBc+ and HBsAg

HBeAg 2 OBS 54

, 71 13% to 67% High

- 2

- 1 0 0 0 0 0 0 Very Low

Anti

- HBc+ and HBsAg

anti

- HBs 2 OBS 72

, 73 0% to 5% High

- 1 0 0 0 0 0 0 0 Moderate

Anti

- HBc+ and HBsAg

anti

- HBc 3 OBS 67

, 68

, 73 0% to 37% High

- 1

- 1 0 0 0 0 0 0 Low104 Definitions
of Donor Positivity Recipient

tested for: Quantity

and Type of
Evidence Range of

Results

Starting Grade Decrease GRADE Increase GRADE

GRADE
of
Evidence
for
Outcome Overall

GRADE
of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Confounders would reduce the effect

Anti

- HBc+ and HBsAg

liver HBV

DNA 2 OBS 67

, 71 0% to 13% High

- 2

- 1 0 0 0 0 0 0 Very Low

Anti

- HBc+ and HBsAg

serum HBV

DNA 6

OBS 54

, 67

, 69

-

71

, 73

, 74 0% to 71% High

- 1

- 1 0 0 0 0 0 0 Low

Anti

- HBc+ and HBsAg

lymphocytes

HBV

- DNA 1 OBS 70 0% High 0

- 1 0 0 0 0 0 0 Moderate

HBV and Kidney T ransplantation

anti

- HBc+ HBsAg 1OBS 63 0% High

- 2 0 0 0 0 0 0 0 Low

Low anti

- HBc+ HBeAg 1 OBS 63 0% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HBc+ anti

- HBc 1OBS 63 0% High

- 2 0 0 0 0 0 0 0 Low

anti

- HBc+ serum HBV

DNA 1 OBS 63 0% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HBc+ anti

- HBs 1 OBS 63 0% High

- 2

- 1 0 0 0 0 0 0 Very Low

HBsAg

- , anti

- HBc+ HBsAg 6 OBS 65

, 66

, 72

, 75

- 78 0% High

- 1 0 0 0 0 0 0 0 Moderate

HBsAg

- , anti

- HBc+ anti

- HBs 4 OBS 72

, 75

, 78

, 79 0% to 11% High

- 1 0 0 0 0 0 0 0 Moderate

HBsAg

- , anti

- HBc+ anti

- HBc 7 OBS 65

, 66

, 72

, 75

- 79 0% to 13% High

- 1 0 0 0 0 0 0 0 Moderate

HBsAg

- , anti

- HBc+ anti

- HBs and

anti

- HBc 1 OBS 78 0% High

- 1

- 1 0 0 0 0 0 0 Low105 Definitions
of Donor Positivity Recipient

tested for: Quantity

and Type of
Evidence Range of

Results

Starting Grade Decrease GRADE Increase GRADE

GRADE
of
Evidence
for
Outcome Overall

GRADE
of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Confounders would reduce the effect

HBsAg

- , anti

- HBc+ “HBV viremia” 1 OBS 79 0% High

- 2

- 1 0 0 0 0 0 0 Very Low

HBsAg

- , anti

- HBc+,
serum HBV

DNA

HBsAg 1 OBS 80 0% High

- 2

- 1 0 0 0 0 0 0 Very Low

HBsAg

- , anti

- HBc+,
serum HBV

DNA

anti

- HBc 1 OBS 80 0% High

- 2

- 1 0 0 0 0 0 0 Very Low

HBsAg

- , anti

- HBc+,
serum HBV

DNA

serum HBV

DNA 1 OBS 80 0% High

- 2

- 1 0 0 0 0 0 0 Very L ow

HBV and Heart T ransplantation

anti

- HBc+ HBsAg 2 OBS 63

, 81 0% to 4% High

- 2 0 0 0 0 0 0 0 Low

Very Low anti

- HBc+ anti

- HBc 2 OBS 63

, 82 18% to 65% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HBc+ anti

- HBs 3 OBS 63

, 81

, 82 8% to 48% High

- 1

- 1 0 0 0 0 0 0 Low

HBsAg

- , anti

- HBc+ HBsAg 1 OBS 65

, 66 0% High

- 2

- 1 0 0 0 0 0 0 Very Low

HBsAg

- , anti

- HBc+,
anti

- HBs+ HBsAg 1 OBS 83

, 84 0% High

- 1

- 1 0 0 0 0 0 0 Low106 Definitions
of Donor Positivity Recipient

tested for: Quantity

and Type of
Evidence Range of

Results

Starting Grade Decrease GRADE Increase GRADE

GRADE
of
Evidence
for
Outcome Overall

GRADE
of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Confounders would reduce the effect

HBsAg

- , anti

- HBc+,

serum HBV

DNA

HBsAg 1 OBS 85 0% High

- 2

- 1 0 0 0 0 0 0 Very Low

HBsAg

- , anti

- HBc+,

serum HBV

DNA

anti

- HBc 1 OBS 85 0% High

- 2

- 1 0 0 0 0 0 0 Very Low

HBsAg

- , anti

- HBc+,

serum HBV

DNA

serum HBV

DNA 1 OBS 85 0% High

- 2

- 1 0 0 0 0 0 0 Very Low

HBsAg

- , anti

- HBc+,

serum HBV

DNA

lymphocyte

HBV

- DNA 1 OBS 85 20% High

- 2

- 1 0 0 0 0 0 0 Very Low

HBV and Lung T ransplantation

HBsAg

- , anti

- HBc+ HBsAg 1 OBS 86 0% High

- 1

- 1 0 0 0 0 0 0 Low

Low HBsAg

- , anti

- HBc+ anti

- HBc 1 OBS 86 0% High

- 1

- 1 0 0 0 0 0 0 Low

HCV and Liver T ransplantation

anti

- HCV+ anti

- HCV 1 OBS 37

, 44 24% High

- 2

- 1 0 0 0 0 0 0 Very Low

Low anti

- HCV+, serum HCV

RNA+ anti

- HCV 1 OBS 87 67% High

- 1

- 1 0 0 0 0 0 0 Low107 Definitions
of Donor Positivity Recipient

tested for: Quantity

and Type of
Evidence Range of

Results

Starting Grade Decrease GRADE Increase GRADE

GRADE
of
Evidence
for
Outcome Overall

GRADE
of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Confounders would reduce the effect

a nti

- HCV+, serum HCV

RNA+ HCV

- RNA 1 OBS 87 100% High

- 1

- 1 0 0 0 0 0 0 Low

HCV and Kidney T ransplantation

anti

- HCV+ anti

- HCV 8 OBS 5

, 39

-

43

, 88

- 94 6% to 91% High

- 2

- 1 0 0 0 0 0 0 Very Low

Very Low anti

- HCV+ HCV

- RNA 2 OBS 91

, 92 50% to 100% High

- 1

- 1 0 0 0 0 0 0 Low

anti

- HCV+, serum HCV

RNA+ anti

- HCV 2 OBS 38

, 96 0% to 19% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HCV+, serum HCV

RNA+ anti

- HCV or

indeterminate 1 OBS 95

, 96 35% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HCV+, serum HCV

RNA+ HCV

- RNA 2 OBS 38

, 95

, 96 0% to 57% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HCV+, serum HCV

RNA+ RIA 1 OBS 38 0% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HCV+
RIBA+ anti

- HCV 1 OBS 97 62% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HCV+
RIBA+ HCV

- RNA 1 OBS 97 67% High

- 2

- 1 0 0 0 0 0 0 Very Low

HCV and Heart T ransplantation108 Definitions
of Donor Positivity Recipient

tested for: Quantity

and Type of
Evidence Range of

Results

Starting Grade Decrease GRADE Increase GRADE

GRADE
of
Evidence
for
Outcome Overall

GRADE
of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Confounders would reduce the effect

anti

- HCV+ anti

- HCV 3 OBS 99

- 103 11% to 24% High

- 2 0 0 0 0 0 0 0 Low

Very Low anti

- HCV+ HCV

- RNA 3 OBS 99

- 103 12% to 75% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HCV+ liver HCV 1 OBS 102 29% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HCV+ “Any HCV

infection” 1 OBS 102 43% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HCV+, serum HCV

RNA+ anti

- HCV 1 OBS 98 44% High

- 2

- 1 0 0 0 0 0 0 Very Low

anti

- HCV+, serum HCV

RNA+ HCV

- RNA 1 OBS 98 100% High

- 2

- 1 0 0 0 0 0 0 Very Low

Note : The shaded rows denote evidence on rates where the donor was positive for anti

- HBc but it was not reported whether the donor was positive for HBsAg; these were considered “critical” outcomes. The only expectation to this was when the recipient was being te sted for anti

- HBs, which was not considered critical. For HCV, we
considered the result critical whenever the donor was positive for HCV RNA (thus the row was shaded).109 

### Question 3: What behavioral risk factors are associated with an increased probability of infection with HIV, HBV, or HCV? What is the prevalence of these characteristics among potential solid organ donors?

Table 3. GRADE Table for Question 3 (Prevalence of Behavioral Risk Factors)

Factor Quantity and Type of

Evidence Findings Starting Grade Decrease GRADE Increase GRADE

GRADE of
Evidence
for
Outcome Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Associated Despite Confounders

Men who have
sex with men 2 OBS* 104

, 105 In two general population studies, one reported that 3.7% of men have sex with another man, 104 while the other reported that 9.3% have a history of having sex
with another man. 135 High 0

- 1

- 1 0 0 0 0 0 Low

Injection drug
abuse 4 OBS 51

, 105

, 106

, 112 All four studies assessed general populations. Reported prevalences of injection drug use were 1.4%, 105 1.7%, 51 3.5%, 112 and 7.9%. 106 The lower two
estimates were derived from NHANES data, and the higher two were drawn from patients and volunteers in urban

areas. Of the injection drug users in one study, 63.2% reported they did not use needle exchange programs. 106 High 0

- 1

- 1 0 0 0 0 0 Low

Sex Work 1 OBS 106 One general population study reported 2.3% of participants reported exchanging sex for money or drugs. 106 High 0

- 1

- 1 0 0 0 0 0 Low

High

- Risk Sex
Partners: Injection drug

user 1 OBS 112 Among general population volunteers from a mainly urban area, 5% reported having sex with an injection drug use. 112 High 0

- 1

- 1 0 0 0 0 0 Low110 Factor Quantity and Type of

Evidence Findings Starting Grade Decrease GRADE Increase GRADE

GRADE of
Evidence for
Outcome Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Associated Despite Confounders

High

- Risk Sex
Partners: Sex
workers 1 OBS 106 In the same population, 7.4% reported
sex with a commercial sex worker. 106 High 0

- 1

- 1 0 0 0 0 0 Low

Multiple Sex
Partners: Multiple
undefined 2 OBS 105

, 112 26% of volunteers in one study reported having sex wi th multiple partners, 112 while 22% of NHANES parti cipants reported having multiple sex partners during the previous year. 105 High 0 0

- 1 0 0 0 0 0 Moderate

Multiple Sex
Partners: At least 2 partners 2 OBS 104

, 223 74% reported having sex with at least two partners, 104 74% reported having
sex with 2

- 49 partners. 105 High 0 0

- 1 0 0 0 0 0 Moderate

Multiple Sex
Partners: At least 50 partners 2 OBS 104

, 105 In one study, 3.5% reported having at least 50 sex partners, 104 while in another 6.6% did. 105 High 0

- 1

- 1 0 0 0 0 0 Low

Age at first intercourse (<18 years) 2 OBS 51

, 104 The proportion of adults who reported having sex at age 18 or younger were 58% 51 and 59% 104 in two general population studies. High 0 0

- 1 0 0 0 0 0 Moderate

Same

- sex partner (not
restricted to men) 1 OBS 106 8.2% of men and women reported having sex with same or both genders. 106 High 0

- 1

- 1 0 0 0 0 0 Low

Noninjection
substance abuse: Ongoing 1 OBS 33 Among potential living donors, 5.5% had unspecified ongoing drug abuse. 33 High 0

- 1 0

- 1 0 0 0 0 Low111 Factor Quantity and Type of

Evidence Findings Starting Grade Decrease GRADE Increase GRADE

GRADE of
Evidence for
Outcome Study Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose - response Associated Despite Confounders

Noninjection
substance abuse: Lifetime 3 OBS 51

, 104

, 105 In the general population, 17% reported lifetime use of drugs other than marijuana, 51 18% reported ever having used any drugs, 105 and 21% reported ever using street drugs/cocaine. 104 High 0 0

- 1 0 0 0 0 0 Moderate

Alcohol 1 OBS 122 Among heart donors, 20% reportedly drank alcohol heavily. 122 High

- 1

- 1 0 0 0 0 0 0 Low

Tobacco 1 OBS 122 Among heart donors, 36% reportedly
used tobacco. 122 High

- 1

- 1 0 0 0 0 0 0 Low

*Observational study112 

### Question 4: What nonbehavioral factors are associated with an increased probability of infection with HIV, HBV, or HCV? What is the prevalence of these factors among potential solid organ donors?

Table 4. GRADE Table for Question 4 (Nonbehavioral Risk Factors)

Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

Factors Identified in Original Guideline Exposure to Infected or Suspected Blood HBV 1 OBS 124 One study of embalmers who had a needle stick injury during embalming did not find an association between needlestick injuries with known or suspected HBV positive bloo d and HBV infection

. 124 Low 0

- 1

- 1

- 1 0 0 0 0 Very Low

HCV No studies

- - - - - - - - - - N ot
A pplicable (NA)

HIV

- - - - - - - - - - - NA Signs and Symptoms HBV No studies

- - - - - - - - - - NA

HCV 1 OBS 121 Jaundice: Associated in one study 121 Low 0

- 1 0 0 0 1 0 0 Low

1 OBS 119 ALT Reactivity: Associated in one study. 119 Low 0

- 1 0 0 0 1 0 0 Low

1 OBS 51 AL T >40 U/L: Associated in one study 51 Low 0

- 1 0 0 0 1 0 0 Low

1 OBS 109 Elevated liver enzyme: Associated in one study 109 Low 0

- 1 0 0 0 0 0 0 Very Low

HIV No studies

- - - - - - - - - - NA113 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders Receipt of Blood Transfusion HBV 3 OBS 111

, 112

, 115 Blood transfusion was associated with HBV infection in a general population, 112 as was blood transfusion before 1991 in a special population. 111 Blood
transfusion was not associated with HBV in another special population study. 115 Lo w 0 0

- 1 0 0 0 0 0 Very Low

HCV 8

OBS 51

, 109

, 112

, 117

, 118

,
120

, 121

, 129 All 8 studies associated having had a blood

transfusion with HCV, and in eight of them the effect
size was large. It was independently associated with HCV with large effect sizes in three blood donor
studies 117

, 120

, 129 and two general population
studies. 112

, 118 Two additional general population study performed univariate analyses only and found large
effect sizes. 109

, 121 The remaining general population study found an independent association between having a blood trans fusion before 1992 and HCV,
but the effect size was not large. 51 Low 0 0 0 0 0 1 0 0 Moderate

HIV No studies

- - - - - - - - - - NA114 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders Accidental Needlestick with Unknown Blood HBV 2 OBS 107

, 112 According to data collected from a low

- quality next

- of

- kin, accidental needle sticks were not associated with HBV among potential corneal donors. 107 A general population study found a lower prevalence of HBV among people who reported a needlestick. 112 Low 0 0 0

- 1 0 0 0 0 Very Low

HCV 4 OBS 107

, 112

, 117

, 120 According to data collected from a low

- quality next

- of

- kin, accidental needle sticks were not associated with HCV among potential corneal donors

. 107 A general population study found a lower prevalence of
H C V among people who reported a needlestick. 112 Among blood donors who work in a healthcare setting, needlestick injuries were not associated with
HC V in one study, 120 but “bloody” needlestick injuries
were in another. 117 Low 0

- 1 0 0 0 0 0 0 Very Low

HIV 1 OBS 107 According to data collected from a low

- quality next

- of

- kin, accidental needle sticks were not associated with HIV among potential corneal donors 107 Low

- 1

- 1 0

- 1 0 0 0 0 Very Low
Hemodialysis HBV 2 OBS 111

, 112 Hemodialysis was associated with HBV in one general population study 112 and one special population study. 111 Both analyses were univariate,
and the special population study had a large effect
size. Low 0 0 0 0 0 1 0 0 Moderate

HCV 3 OBS 112

, 118

, 121 In general population studies, “kidney dialysis” was
associated with HCV in a univariate analysis in one study, 121 and hemodialysis was associated with HCV with a large effect size in multivariate analysis in a second study. 112 A third study did not find an association between hemodialysis and HCV. 118 Low 0 0 0 0 0 0 0 0 Low

HIV No studies

- - - - - - - - - - NA115 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

Surgery HBV 3 OBS 107

, 112

, 116 The corneal donor study did not associate having had surgery with HBV. 107 One general population study found a lower prevalence of HBV among people who had surgery, 112 and another found no relationship. 116 Low 0

- 1 0 0 0 0 0 0 Very Low

HCV 5

OBS 107

, 109

, 112

, 117

, 11

9 The corneal donor study did not associate having

had surgery with HCV. 107 One blood donor study did not find any association with recent surgery 119 and one general popula tion study did not find any association with history of surgery. 109 However, one
blood donor study did find an independent association between HCV and lifetime history of surgery (or sutures). 117 A general population study
found no association. 112 Low 0

- 1 0 0 0 0 0 0 Very Low

HIV 1 OBS 107 The corneal donor study did not associate having had surgery with HIV. 107 Low

- 1

- 1 0

- 1 0 0 0 0 Very Low Organ Transplant Recipients HBV 2 OBS 107

, 113 HBV was not associated with having a organ transplant in one very low

- quality study 107 or

a special population study. 113 Low 0 0 0

- 1 0 0 0 0 Very Low

HCV 1 OBS 107 HCV was not a ssociated with having a organ transplant in one very low

- quality study. 107 Low

- 1

- 1 0

- 1 0 0 0 0 Very Low

HIV 1 OBS 107 HCV was not associated with having a organ transplant in one very low

- quality study. 107 Low

- 1

- 1 0

- 1 0 0 0 0 Very Low Acupuncture HBV 2 OBS 113

, 116 Neither the general population study 116 nor the special population study 113 found an association between HBV and acupuncture. Low 0 0 0 0 0 0 0 0 Low

HCV 3 OBS 118

, 120

, 129 Acupuncture was not associated with HCV infection
in two studies of blood donors 120

, 129 or one study of a general population. 118 Low 0 0 0 0 0 0 0 0 Low116 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

HIV No studies

- - - - - - - - - - NA Dental Work HBV 1 OBS 116 Dental work within the last six months was not associated with acute HBV in one general population study. 116 Low 0 0 0

- 1 0 0 0 0 Very Low

HCV 2 OBS 117

, 119 Dental work was not associated with HCV amon g blood donors in one study 117 ; nor was having dental work in the six months before donation in another. 119 Low 0 0 0 0 0 0 0 0 Low

HIV No Studies

- - - - - - - - - - NA Blood Draws HBV 1 OBS 107 The corneal donor study did not find an association between HIV testing and HBV, based upon next

- of

kin interviews. 107 Low

- 1

- 1 0

- 1 0 0 0 0 Very Low

HCV 2 OBS 107

, 121 The low

- quality corneal donor study did not find an association between HIV testing and HCV, based upon next of

- kin interviews

. 107 One general population study did find an association between having had a blood test for HBV and having an HCV
infection. 121 The same study also found that being a
blood donor was associated with reduced risk of
HCV. 121 Low 0 0 0

- 1 0 0 0 0 Very Low

HIV 1 OBS 107 The corneal donor study did not find an association between HIV testing and HIV, based upon next of

- kin
interviews. 107 Low

- 1

- 1 0

- 1 0 0 0 0 Very Low117 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

Household Exposure HBV 5 OBS 111

, 115

, 116

, 125

, 12

6 Having household contact with someone with

hepatitis was associated with HBV in a special population study 111 , as was a family history of HBV in another special population study. 125 However, having a household member with hepatitis was not
associated with HB V in a third special population study; 115 nor was being the wife of a man with HBV in a fourth special population study. 126 Sharing a razor
or toothbrush with a household member was not associated with HBV in a general population study
either. 116 Low 0

- 1

- 1 0 0 0 0 0 Very Low

HCV 3 OBS 109

, 1 17

, 121 In one blood donor study, living with someone w ith hepatitis or having a relative with hepatitis was not
associated with HCV , but living with a transfusion recipient and sharing a toothbrush or razor with person(s) unspecified was. 117 In general population studies, having at least one family member treated for viral hepatitis was not associated with an increased risk of HCV in one study, 109 but having at least one family member with HCV in another study

was. 121 Low 0

- 1 0 0 0 0 0 0 Very Low

HIV No studies

- - - - - - - - - - NA118 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

Other Infections HBV 2 OBS 111

, 122 HBV surface antigen positivity was associated with HCV infection among heart donors in one study. 122 HBV infection was associated with having had a sexually transmitted disease (STD) in a special population study. 111 Low 0 0 0 0 0 0 0 0 Low

HCV 6 OBS 51

, 118

- 121

, 129 HCV was significantly associated with history of STD
in two blood donor studies 120

, 129 but not a general population study. 121 HCV was associated with having a STD within six months of donating in another blood donor study. 119 Herpes infection was associated with HCV in a general population study

. 51 In addition, HCV was associated with seropositivity for other
reactive infectious diseases in two blood donor
studies. 119

, 129 HIV infection was not associated with HCV infection upon univariate analysis of a general population study. 118 Low 0

- 1 0 0 0 0 0 0 Very Low

HIV 4 OBS 104

- 106

, 108 In general population studies, HIV infecti on was associated with diagnosis of STD in one study

, 106
HSV

- 2 in two studies

, 104

, 105 and syphilis or other infection not apparently related to HIV in another study, 108 Low 0 0 0 0 0 0 0 0 Low

Sex HBV 6 OBS 111

-

113

, 125

, 127

, 128 In one general population study 112 and 2 special

population studies 113

, 125 males had higher prevalence of HBV. Two additional special populations s tudies
found no difference 127 or a lower prevalence. 111
A study of children found no difference. 128 Low 0

- 1

- 1 0 0 0 0 0 Very Low

HCV 9 OBS 51

, 109

, 112

, 119

-

122

, 129

, 130 One organ donor study found an increased

prevalence of HCV in males. 122 Among blood donors it was in one study 129 but not in two others. 119

, 120
Four general population studies found an increased risk among males. 51

, 112

, 121

, 130 but one other did not. 109 Low 0

- 1 0 0 0 0 0 0 Very Low119 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

HIV 3 OBS 106

, 123 None of three general population studies associated male sex with an increased prevalence of HIV. 106

, 123 Low 0 0 0 0 0 0 0 0 Low

Age HBV 8 OBS 111

- 114

, 124

- 127 Every study tested the association of HBV and age in different ways, and the results are inconsistent and difficult to compare.
One general population study found an increased risk of HBV when >60 years. 112 The rest of the studies were special population studies. One found an
associ ation with mean age (with older people having greater prevalence of HBV) 11 1 while another did
not. 113 Increased prevalence was associated with

age young er than 20 years, 126 age over 35 years, 124 and age over 50 years. 114 In another study lower prevalence was found in people under 49 years. 127 The remaining study did not find any association between age and HBV. 125 Low 0

- 1

- 1 0 0 0 0 0 V ery Low

HCV 7 OBS 109

, 112

, 119

-

122

, 130 Every study tested the association of HCV and age in

different ways, and the results are inconsistent and difficult to compare. The organ donor study found
that HCV infection was associated with older median

age. 122 One of the blood donor studies associated HCV with older mean age, 119 the other did not. 120
In general population studies, HCV was associated with increased mean age 130 and decade of birth (with people born betw een 1940 and 1959 having the highest prevalence), 121 but not age less than
50 years 109 or age less than 60 years. 112 Low 0

- 1 0 0 0 0 0 0 Very Low120 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

HIV 3 OBS 106

, 108

, 123 The HIV studies also measured age in different ways, complicating comparison. In general these studies found young adults to be at the highest risk. One study found younger a dults (aged 18 to 30) had increased prevalence of HIV, 123 another found adults aged 25 to 40 had higher prevalence of HIV than younger people aged 15 to 24 years, 106 and the third found increased prevalence among adults aged 35 to 44 years. 108 Low 0

- 1 0 0 0 0 0 0 Low

Race or Ethnicity HBV 2 OBS 112

, 113 White race or Hispanic ethnicity was associated with lower HBV prevalence in a general population study
in a multivariate anal ysis 112 but not in a special population study. 113 Low 0

- 1 0

- 1 0 0 0 0 Very Low

4 OBS 110

, 111

, 113

, 114 Non

- Hispanic Black race was associated with a

higher prevalence of HBV in a general population study multivariate analysis 110 and two special population studies 111

, 114 but not another special population study. 113 Low 0 0

- 1 0 0 0 0 0 Very Low

3 OBS 110

, 111

, 113 Being Mexican

- American was not associated with a

different prev alence of HBV than non

- Hispanic White race in a multivariate analysis of a general population study. 110 In special population studies, Hispanic ethnicity 113 and Hispanic or Latino ethnicity 111 w ere not associated with HBV infection. Low 0 0

- 1 0 0 0 0 0 Very Low

1 OBS 111 A special population study found an increased

prevalence of HBV among Asian Americans compared with non

- Hispanic White Americans. 111 Low 0

- 1

- 1 0 0 0 0 0 Very Low

1 OBS 116 Among African American, Caucasian, Asian, and

Hispanic children who received blood transfusions, the prevalence was not significantly different. Low 0 0 0

- 1 0 0 0 0 Very Low121 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

HCV 7 OBS 51

, 119

-

122

, 129

, 130 Because about half of the studies combined races in

analyses (their results presented first), the different analyses are reported together here. The different analysis methods complicate side

- by

- side comparison, but the evidence rating wou ld always be „very low‟ for these studies. (These results are all presented in the same row because of overlap within the studies.)
In organ donors, no relation between race and HCV
infection was detected. 122 Three general population studies did not find any relation either. 51

, 121

, 130

White race was not associated with a difference in rate of HCV compared with other races. 119

Black race was associated with increased rates of HCV compared to White race in two studies. 120

, 129
Being Asian was associated with having a lower prevalence of HCV compared to White race among blood donors. 129
Among blood donors, one study found that Hispanic ethnicity had a higher risk of HCV than White

race

, 129 but another did not. 119 Low 0

- 1 0 0 0 0 0 0 Very Low

HIV 3 OBS 105

, 106

, 123 In univariate analyses, two general population studies found increased prevalence of HIV among people of Black race 105

, 106 but a third did not. 123 Low 0

- 1 0 0 0 0 0 0 Very Low

2 OBS 105

, 106 In univariate analyses, neither of two general

population studies found a difference in HIV prevalenc e in White race and Asians. 105

, 106 Low 0 0 0

- 1 0 0 0 0 Very Low122 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders
National Origin/Birthplace HBV 5 OBS 110

, 112

, 116

, 125

, 12

6 National origin and birthplace wer e reported

differently among studies and most factors cannot be
considered side

- by

- side. However, since the rating for any factor in this group will be „very low‟ and there is some overlap among studies, we present the findings together.

In multivariate an alysis of general populations, HCV was associated with being born in Southeast Asia or Africa in one study. 112 A special population study found children born in Korea had higher prevalence
of HBV than children born in the U.S. 126 Other spec ial population studies did not find significantly different
rates of Asian Americans born in East Asia (excluding China) or Southeast Asia or Pacific Islands compared to Asian Americans born in
China. 125
Birth in an area with a high endemic rate or household exposure to someone born in a high endemic rate was not in another general population study. 116
In multivariate analyses, a general population study 110 and a special population study 125 found that being born in the U.S. was ass ociated was lower prevalence of HBV. Low 0

- 1

- 1 0 0 0 0 0 Very Low123 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

HCV 5

OBS 51

, 112

, 119

, 121

, 129 One blood donor study did not associate foreign birth

with HCV, 119 but another did in a multivariate analysis. 129 A general population study found people born outside of the U.S. had a lower prevalence of
HCV. 51 Birth in Southeast Asia or Africa was not associated with an increased prevalence of HCV in another general population study. 112 A general population study found no association bet ween HCV and U.S. citizenship. 121 Low 0

- 1 0 0 0 0 0 0 Very Low

HIV No studies

- - - - - - - - - - NA Preferred Language HBV No studies

- - - - - - - - - - NA

HCV 1 OBS 130 One general population study found an association between preference of English or Spanish and
HCV. 130 Low 0

- 1 0 0 0 0 0 0 Very Low

HIV 1 OBS 123 One general population study found no difference in prevalence of HIV among Spanish speakers. 123 Low 0

- 1 0

- 1 0 0 0 0 Very Low

Occupation HBV 6 OBS 110

- 113

, 115

, 116 Occupation as a health care worker was protective against HBV in one general population study 112 and not associated with HBV in another general population study 110 or a special population study. 113 However, having a healthcare

- related job with frequent blood exposure was associated with HBV in one special population study. 111
Another general population study did not associate healthcare employment or household contact with someone who is a health care worker with HBV, 116 and a special population study did not associate being a health care worker or the sp ouse of one with
HBV. 115 Low 0 0 0 0 0 0 0 0 Low124 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

1 OBS 110 Ever being in the mili t ary was not associated with

HBV in a general population study. 110 Low 0 0 0

- 1 0 0 0 0 Very Low

HCV 2 OBS 109

, 117 In any occupation, occupational blood exposure was associated with HCV among blood donors in one study, 117 but work contact with blood was not associated with HCV in a general population study. 109 Low 0

- 1 0

- 1 0 0 0 0 Very Low

2 OBS 112

, 119 Medical or dental job with frequent blood contact was

not associated with HCV in one blood donor study 119 and was associated with lower prevalence of HCV in a general population study. 112 Low 0

- 1 0

- 1 0 0 0 0 Very Low

2 OBS 51

, 109 Neither of two general population studies associated

ever having served in the armed forces with
HCV. 51

, 109 Low 0 0 0

- 1 0 0 0 0 Very Low

2 OBS 119

, 121 Public safety job with frequent blood contact was not

associated with HCV in one blood donor study. 119 Another study did associate having a job at a prison with having HCV

. 121 Low 0

- 1 0 0 0 0 0 0 Very Low

HIV No studies

- - - - - - - - - - NA Education HBV 3 OBS 110

, 111

, 113 Having less than a high school education was
associated with HB V in one general population study, compared with some college. 110 In special population studies, one found a higher prevalence of HBV among students in 2

- year colleges compared to
those in 4

- year colleges, 111 and the other study found no relationship between years of education and
HBV. 113 Low 0

- 1

- 1 0 0 0 0 0 Very Low125 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

HCV 5 OBS 51

, 119

- 121

, 130 One blood donor study associated less education with HCV, 119 and another associated having no college education with having HCV. 120 One general population study associated having fewer than
12 years of education with having HCV, 51 but two others found no association between educational
attainment and HCV. 121

, 130 Low 0

- 1 0 0 0 0 0 0 Very Low

HIV 2 OBS 104

, 106 Neither of two general population studies found an association between having less than a high school education and having H I V. 104

, 106 Low 0 0 0

- 1 0 0 0 0 Very Low
Economic Factors HBV 2 OBS 113

, 114 One special population study did not associate
homelessness with HBV. 113 Another special population study did not associate homelessness, institutionalization, or other non

- independent living arrangement with HBV. 114 Low 0 0

- 1

- 1 0 0 0 0 Very Low

HCV 2 OBS 51

, 121 In a general population, ever having been homeless

was a ssociated with an increased risk of HCV. 121
In the same study, annual income was not
associated with HCV.
Another general population study did not find any
association with family poverty level and HCV. 51 Low 0

- 1 0

- 1 0 0 0 0 Very Low

HIV 2 OBS 104

, 123 Being homeless was associated with an increased prevalence of HIV in one general population study. 123 In another general population study, having a poverty index of less than one was not associated with
HIV. 104 Low 0

- 1 0 0 0 0 0 0 Very Low

He alth Ins ura nce HBV No studies

- - - - - - - - - - NA126 Factor Virus Quantity and

Type of
Evidence Findings Starting
Grade Decrease Grade Increase Grade

GRADE
of
Evidence
for
Outcome Overall Quality Consistency Directness Precision Publication Bias Large Magnitude

Dose Response Associated Despite Confounders

HCV 1 OBS 130 One general population study associated insurance with HCV infection, with people on Medicaid having the highest prevalence. 130 Low 0

- 1 0 0 0 0 0 0 Very Low

HIV 2 OBS 106

, 123 One general population study found a higher prevalence of HIV among people with no insurance 106
but a second did not. 123 Low 0

- 1 0

- 1 0 0 0 0 Very Low Marital Status HBV 2 OBS 110

, 114 Being divorced or separated was asso ciated with a higher prevalence of HBV than any other status in one general population study. 110 Being currently married was not associated with any difference in HBV prevalence than any other status in one special population study. 114 Low 0 0 0 0 0 0 0 0 Low

HCV 1 OBS 117 Being married was associated with a lower risk of HCV in one blood donor study. 117 Low 0 0 0 0 0 0 0 0 Low

HIV 1 OBS 104 Being married or cohabitating was associated with a lower risk of HIV in one general population study. 104 Low 0 0 0 0 0 0 0 0 Low127 

### Question 5: What are the test characteristics of the screening methods available to detect HIV, HBV, and HCV in potential solid organ donors? Do test characteristics differ in particular populations and with donor clinical status (i.e., heart beating vs. non

- heart beating donors OR adult vs. pediatric do nors)?

Table 5.GRADE Table for Question 5 (Performance

- Sensitivity/Specificity)

Virus Test Trade Name Manufacturer Quantity and Type of
Evidence Findings (Point

Estimates) Starting
GRADE (Study Design ) Decrease GRADE GRADE for
Evidence for
Outcome Quality Consistency Directness Precision

Publication
Bias

Tests currently in use in U.S. Organ Procurement Organization 176 : Immunoassays

HIV
3 rd generation
EIA Genetics System

(GS) HIV

- 1/ HIV

- 2
Plus 0 EIA Bio

- Rad

Laboratories 1 A* 132 Sensitivity: 99.8%A**
Specificity: 99.4%A

Main limitations: lack of diagnostic uncertainty,

no blinding Moderate

- 1 0 0 0 0 Low

HIVAB HIV

- 1/HIV

- 2 (rDNA) EIA Abbott

Laboratories 2 A 131

, 132 Sensitivity: 99.4%A 132 and 100%A 131
Specificity: 97.7%A 132 and 99.74%A 131

Main limitations: lack of diagnostic uncertainty, no blinding.
Study design and quality assessment equal for the
two studies

. Moderate

- 1 0 0 0 0 Low

HBV (H B sAg; the surface antigen) Abbott AxSYM

H B sAg Assay Abbott

Laboratories 1 CDx † 155 Sensitivity: 100%C‡

Specificity: 99.4%C

Main limitation: no blinding High

- 1 0 0 0 0 Moderate

Abbott PRISM
HB sAg Abbott

Laboratories No studies

- - - - - - - -128

Virus Test Trade Name Manufacturer Quantity and Type of
Evidence Findings (Point

Estimates) Starting
GRADE (Study Design ) Decrease GRADE GRADE for
Evidence for
Outcome Quality Consistency Directness Precision

Publication
Bias

ADVIA Centaur
HB sAg Assay Siemens

Healthcare Diagnostics 1 A 156 Sensitivity: 100%A

Specificity: 97.9%A

Main limitations: lack of diagnostic uncertainty,

no blinding Moderate

- 1 0 0 0 0 Low

Genetic Systems (GS) HBsAg EIA 3.0 Bio

- Rad

Laboratories No studies

- - - - - - - -

HBV (anti

- HBs;
antibodies to the surface antigen) Ortho Antibody to

HBsAg ELISA Test System 3 Ortho Clinical

Diagnostics No studies

- - - - - - - -

HBV (anti

- HBc;
antibodies to
the core antigen) Abbott PRISM

HBcore Abbott

Laboratories No studies

- - - - - - - -

ADVIA Centaur HBc Total Assay Siemens

Healthcare Diagnostics No studies

- - - - - - - -

AxSYM Core 2.0 Abbott

Laboratories No studies

- - - - - - - -

CORZYME Abbott

Laboratories No studies

- - - - - - - -

Ortho HBc ELISA Test System Ortho Clinical

Diagnostics No studies

- - - - - - - -129

Virus Test Trade Name Manufacturer Quantity and Type of
Evidence Findings (Point

Estimates) Starting
GRADE (Study Design ) Decrease GRADE GRADE for
Evidence for
Outcome Quality Consistency Directness Precision

Publication
Bias

HCV Abbott HCV EIA 2.0 Abbott
Laboratories 3 CDx 166

- 168 Sensitivity: 73.2%C 1 66

, 85.7%C 168 , 100%C 167
Specificity: 92.7%C 167

, 99.8%C 168 , 99.9%C 166

Main limitations: one study less appropriate reference standard, no blinding in

any.

Anderson et al. 166 used a
less reliable reference
standard. All other factors in study design and
limitations assessment the same for all three studies. High

- 1 0 0 0 0 Moderate

ADVIA Centaur HCV

assay Siemens

Healthcare Diagnostics 1 A 172

1 DxC 171 Sensitivity: Both 100%

Specificity: 94.4%C 171

, 99.9%A 172

Main limitations: one study suboptimal enrollment methods, no blinding in
either.

Denoyel et al. 172 did not report appropriate
enrollment methods.
All other study design and
limitations assessments
were the same. High

- 1 0 0 0 0 Moderate

AxSYM Anti

- HCV Abbott

Laboratories No studies

- - - - - - - -130

Virus Test Trade Name Manufacturer Quantity and Type of
Evidence Findings (Point

Estimates) Starting
GRADE (Study Design ) Decrease GRADE GRADE for
Evidence for
Outcome Quality Consistency Directness Precision

Publication
Bias

Ortho HCV
Version 3.0 ELISA Test System Ortho Clinical

Diagnostics 2 CDx 169

, 171

1 A 170 Sensitivity: All three 100%C

Specificity: 95.5%C 171

, 99.7%C 169 , 99.9%A 170

Main limitations: one study lack of diagn ostic uncertainty, one study suboptimal enrollment methods, no blinding.

Vrielink et al. 170 did not use samples with dia gnostic uncertainty or report adequate enrollment
methods. The rest of the study design and limitations
assessment factors were
the same for all three
studies. High

- 1 0 0 0 0 Moderate131

Virus Test Trade Name Manufacturer Quantity and Type of
Evidence Findings (Point

Estimates) Starting
GRADE (Study Design ) Decrease GRADE GRADE for
Evidence for
Outcome Quality Consistency Directness Precision

Publication
Bias

Tests currently in use in U.S. Organ Procurement Organization 176 : NAT

HIV NAT COBAS AmpliScreen

HIV

- 1 Test v. 1.5 Roche

Diagnostics 1 DxC 142

1 A 132 Sensitivity: 7.7%C 142 and

92.6% A 132

Spe cificity: 96.9%A 132 and 100%C 142

Main limitations: one study inappropriate reference standard, other lack of diagnostic un certainty,
neither blinded

The main difference in findings appears to be due
to the use of a reference standard inappropriate to calculate sensitivity in Bamaga et al. 142 Moderate

- 1 0 0 0 0 Low

HCV NAT COBAS AmpliScreen

HCV Test version.
2.0 Roche

Diagnostics 1 CDx 142 Sensitivity: 20%C

Specificity: 99.4%C

Main limitations: inappropriate reference standards, no blinding Moderate

- 1 0 0 0 0 Low

HBV NAT COBAS Ampli S creen

HBV Test Roche

Diagnostics 1 CDx 164 Sensitivity: 84.8% C

Specificity: 100%C

Main limitations:

no blinding, potential for publication bias Moderate

- 1 0 0 0

- 1 Very Low132

Virus Test Trade Name Manufacturer Quantity and Type of
Evidence Findings (Point

Estimates) Starting
GRADE (Study Design ) Decrease GRADE GRADE for
Evidence for
Outcome Quality Consistency Directness Precision

Publication
Bias

HCV and
HIV

- 1 NAT ProCleix HIV

- 1/

HCV Assay Gen

- Probe

Incorporated 1 CDx 136

1 A 135 HIV

Sensitivity: 99.9%A 135 and 100%C 136

Sp ecificity: 99.67%A 135 and 100%C 136

HCV

Sensitivity: 99.3%C 136 and 99.6%A 135
Specificity: 97.4%C 136 and 99.6%A 135

Main limitations: one study lack of diagnostic uncertainty, one study

no blinding, potential for publication bias

. Vargo et al. 135 did not have diagnostic u ncertainty, and
Jackson et al. did not have blinding. The studies were on the same for the rest of the study design and
limitations assessment
factors. Moderate 0 0 0 0

- 1 Low133

Virus Test Trade Name Manufacturer Quantity and Type of
Evidence Findings (Point

Estimates) Starting
GRADE (Study Design ) Decrease GRADE GRADE for
Evidence for
Outcome Quality Consistency Directness Precision

Publication
Bias

Tests currently not in use in U.S. Organ Procurement Organization 176 : 4 th generation Immunoassays

HIV
4 th generation ARCHITECT HIV

Combo Abbott

Laboratories 2 A 145

, 150 Sensitivity: Both 100%A

Specificity: 99.6%A 145 and 100%A 150

Main limitations: lack of diagnostic uncertainty, suboptimal enrollment methods, no blinding.

The study design and
limitations assessments
were the same for both
studies. Moderate

- 1 0 0 0 0 Low134

Virus Test Trade Name Manufacturer Quantity and Type of
Evidence Findings (Point

Estimates) Starting
GRADE (Study Design ) Decrease GRADE GRADE for
Evidence for
Outcome Quality Consistency Directness Precision

Publication
Bias

AxSYM HIV Ag/Ab
Combo Abbott

Laboratories 1 CDx 144

3 A 145

, 147

, 148 Sensitivity: All 100%

Specificity: 98%A, 145 99.65%C, 144 99.8%A, 147 99.9%/99.87%A 148 (last two from same study, different data sets)

Main limitations: two studies lack of diagnostic uncertainty and/or suboptimal enrollment methods, all studies no blinding.

Bourlet e t al. 144 had diagnostic uncertainty and appropriate enrollment
methods while the rest did
not. The studies were the same on all other study design and limitations assessment factors. Moderate

- 1 0 0 0 0 Low

COBAS Core HIV
Combi Roche

Diagnostics 2 A 149

, 150 Sensitivity: Both 100%A

Specificity: 99.3%A 150 and 99.73%A 149

Main limitations: lack of diagnostic uncertainty,

one study suboptimal enrollment methods,
both no blinding.

The two studies were the same for study design and
limitations assessment. Moderate

- 1 0 0 0 0 Low135

Virus Test Trade Name Manufacturer Quantity and Type of
Evidence Findings (Point

Estimates) Starting
GRADE (Study Design ) Decrease GRADE GRADE for
Evidence for
Outcome Quality Consistency Directness Precision

Publication
Bias

Coulter HIV

- 1 p24 Antigen Assay Coulter

Corporation No studies

- - - - - - - -

Enzygnost HIV Integral II Siemens

Healthcare Diagnostics No studies

- - - - - - - -

Genscreen Plus HIV Ag/Ab Combo Bio

- Rad

Laboratories 1 DxC 143

1A 147 Sensitivity: Both 100%

Specificity: 82.5%C, 143 99.9%A 147
Main limitations: One study lack of diagnostic uncertainty, one suboptimal enrollment methods,
neither blinded.

Ly et al. 147 did not have diagnostic uncertainty or report appropriate

e nrollment methods.
All other study design and
limitation assessment
factors were the same. High

- 1 0 0 0 0 Moderate

Genscreen HIV Ultra Ag

- Ab Assay Bio

- Rad

Laboratories 1 A 150 Sensitivity:100%A
Specificity: 99.8%A

Main limitations: lack of diagnostic uncertainty, suboptimal enrollment methods, blinding Moderate

- 1 0 0 0 0 Low

Modular HIV Comb i Roche

Diagnostics No studies

- - - - - - - -136

Virus Test Trade Name Manufacturer Quantity and Type of
Evidence Findings (Point

Estimates) Starting
GRADE (Study Design ) Decrease GRADE GRADE for
Evidence for
Outcome Quality Consistency Directness Precision

Publication
Bias

Murex HIV Ag/Ab
Combo Abbott

Laboratories 1 A 150 Sensitivity: 100%A

Specificity: 99.6%A

Main limitations: lack of diagnostic uncertainty, suboptimal enrollment
method s, blinding Moderate

- 1 0 0 0 0 Low

VIDAS DUO QUICK bioMerieux

Clinical Diagnostics No studies

- - - - - - - -

VIDAS DUO ULTRA bioMerieux

Clinical Diagnostics 2 DxC 144

, 151

1 A 150 Sensitivit y: All 100%

Specificity:99.5%C, 150 99.5%A, 151 99.86%C 144

Main limitations: one study lack of diagnostic uncertainty, one study suboptimal enrollment methods, two studies lack of blinding

Ly et al. 150 did not have diagnostic uncertainty or report appropriate
enrollment methods. None of the studies besides
Saville et al. 151 used blinding. All other study design and limitation
assessment fa ctors were
the same. High

- 1 0 0 0 0 Moderate137

Virus Test Trade Name Manufacturer Quantity and Type of
Evidence Findings (Point

Estimates) Starting
GRADE (Study Design ) Decrease GRADE GRADE for
Evidence for
Outcome Quality Consistency Directness Precision

Publication
Bias

Vironostika HIV
Uni

- Form II Ag/Ab bioMerieux

Clinical Diagnostics 3 CDx 152

, 224

, 225

1 A 147 Sensitivity: All 100%

Specificity: 99.2%C, 152 99.3%C, 225 99.4%C, 224 99.6%A 147

Main limitations: one study lack of diagnostic uncertainty, no blinding

Ly et al. 147 did not have diagnostic uncertainty or report appropriate
enrollment methods.
All other study design and
limit ation assessment factors were the same. High

- 1 0 0 0 0 Moderate

HCV
4 th generation INNOTEST HCV Ab

IV Innogenetics

NV No studies

- - - - - - - -

Monolisa HCV Ag/Ab
Ultra Bio

- Rad

Laboratories No studies

- - - - - - - -

Murex 4.0 Abbott

Laboratories No studies

- - - - - - - -

* A: Analytic study

** A: Analytic sensitivity/specificity
† CDx: Clinical diagnostic cohort ‡ C: Clinical sensitivity/specificity138 

### Question 6: Which donor interventions reduce the probability of pathogen transmission from an organ donor infected with HIV, HBV, or HCV to a previously uninfected recipient?

Table 6. GRADE Table for Question 6 (Inactivation)

Comparison Outcome Quantity and Type of
Evidence Findings Starting Grade Decrease GRADE Increase GRADE

GRADE of
Evidence f or Outcome Study Quality Consistency Directness Precision Publication Bias Large Magnitude Dose Response Confounders would reduce the effect

Inactivating vs. not inactivating pathogens in solid organs Viral

burden One study 180

, 181 The four
inactivation procedures
reduced viral
burden 69%%
to 99.7% Low

- 1

- 1 0 0 0 +1 +1 0 Low139 

### Question 7: How do the clinical outcomes of recipients of organs from donors infected with HIV, HBV, or HCV compare to those who remain on the transplant list?

Table 7

. GRADE Table for Question 7 (Clinical Outcomes of Known Positive Organs vs. Waitlist or Known Negative O rgans )

Comparison Outcome Quantity and Type of
E vidence Findings Starting G rade Decrease GRADE Increase GRADE

GRADE of
Evidence
for
Outcome Overall

GRADE of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude Dose R esponse Confounders would reduce the effect

Receiving an HCV+ organ compared to remaining
on the waitlist Recipient
survival One

observational study 189 Adjusted hazard ratio 0.76

(95% CI: 0.6 to 0.96) (in favor of transplantation over the waitlist) Low

- 1

- 1 0 0 0 0 0 0 Very Low Ve ry Low

Receiving an HBV+ organ compared to receiving a negative organ for recipients who were
NEGATIVE before transplant Graft
survival One

observational study 77 Results favored receiving

an organ from a negative
donor:
1 year: D+ 87%, D

- 88%
2 yrs.: D+ 78%, D

- 83%
3 yrs: D+ 72%, D

- 77% Low

- 1

- 1 0 0 0 0 0 0 Very Low

Very Low Recipient
survival One

observational study 77 Results favored receiving

an organ from a negative
donor:
1 year: D+ 94%, D

- 94%
2 yrs.: D+ 90%, D

- 92%
3 yrs: D+ 86%, D

- 90% Low

- 1

- 1 0 0 0 0 0 0 Very Low140 Comparison Outcome Quantity and Type of
E vidence Findings Starting G rade Decrease GRADE Increase GRADE

GRADE of
Evidence for
Outcome Overall

GRADE of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude Dose R esponse Confounders would reduce the effect

Receiving a HCV+ organ compared to receiving a negative organ for recipients who were
NEGATIVE before transplant Graft
survival Three

observational
studies 44

, 182

, 18

3

, 190

, 191 No statistically significant

difference was reported by any of the three studies. Low

- 1 0 0 0 0 0 0 0 Very Low

Low Recipient
survival Three

observational
studies 44

, 99

, 101

,
182

, 183 Two of the three studies

reported results in favor of receiving an organ from a negative donor. The third study found a statistically nonsignificant result. Low

- 1 0 0 0 0 +1 0 0 Low141 Comparison Outcome Quantity and Type of
E vidence Findings Starting G rade Decrease GRADE Increase GRADE

GRADE of
Evidence for
Outcome Overall

GRADE of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude Dose R esponse Confounders would reduce the effect

Receiving an HBV+ organ compared to rece iving a negative organ for recipients who were
POSITIVE before transplant Graft
survival Four

observational
studies 75

, 77

, 185

-

188 Only one of the four studies

reported any statistically significant difference. This study found that if the kidney donor was living, results slightly favored receiving an organ from an HBsAg+ donor, whereas if the kidney donor was deceased, results favored receiving an organ from an HBsAg

- donor. Low

- 1

- 1 0 0 0 0 0 0 Ve ry Low

Very Low Recipient
survival Three

observational
studies 77

, 185

-

188 Only one of the three

studies reported any statistically significant difference. This study found that if the kidney donor was living, there was no statistically significant difference, whereas if the
k idney donor was deceased, results favored receiving an organ from an HBsAg

- donor. Low

- 1

- 1 0 0 0 0 0 0 Very Low142 Comparison Outcome Quantity and Type of
E vidence Findings Starting G rade Decrease GRADE Increase GRADE

GRADE of
Evidence for
Outcome Overall

GRADE of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude Dose R esponse Confounders would reduce the effect

Receiving a HCV+ organ compared to receiving a negative organ for recipients who were
POSITIVE before transplant Graft

sur vival 13

observational
studies 37

, 44

, 182

-

184

, 188

, 190

- 199 No statistically significant

difference was reported by any of the 13 studies. Low

- 1 0 0 0 0 0 0 0 Very Low

Very Low Recipient
survival 11

observational
studies 37

, 44

, 182

-

184

, 188

, 192

-

195

, 197

- 199 Only 2 of t he 11 studies

found any statistically significant difference.
One of the two favored recipients of organs of positive donors, and the other favored recipients of organs of negative donors. Low

- 1 0 0 0 0 0 0 0 Very Low

Note : The shaded rows denote recipient survival, which was considered a “critical” outcome. Graft survival is unshaded because it was not considered “critical” for the purpose of evidence grading.143 

### Q uestion 8: How do the clinic al outcomes of transplant recipients who receive organs from donors with behavioral or nonbehavioral risk factors compare to those who remain on the transplant list?

Table 8

. GRADE T able for Question 8 (Clinical Outcomes of At

- risk Organs vs. Waitlist or Not

- at

- risk O rgans )

Comparison Outcome Quantity and
T ype of
E vidence Findings Starting G rade Decrease GRADE Increase GRADE

GRADE of
Evidence
for
Outcome Overall

GRADE
of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude Dose R esponse Confounders would reduce the effect

Transplant vs. discard kidneys
from at

- risk
donors who test negative R ecipient

survival One

simulation 200 91% survival in

both groups at

one year.

At five years, survival was 68% for the transplant group and 65% for the discard group.

At 10 years,
survival was 49% for the transplant group and 45% for the discard group.

At 20 years,
survival was 23% for the transplant group and 20% for the discard group

. Very

Low 0

- 1 0 0 0 0 0 0 Very Low

V ery Low144 Comparison Outcome Quantity and
T ype of
E vidence Findings Starting G rade Decrease GRADE Increase GRADE

GRADE
of
Evidence
for
Outcome Overall

GRADE
of
Evidence
Base Study Quality Consistency Directness Precision Publication Bias Large Magnitude Dose R esponse Confounders would reduce the effect

Quality of
life One

simulation 200 5.6 QALYs for the

trans plant strategy, compared to
5.1 QALYs for the
discard st rategy Very

Low 0

- 1 0 0 0 0 0 0 Very Low

Waitlist survival
vs. survival of infected recipients
of at

- risk organs Recipient

survival One

simulation 201 One

- year w aitlist

mortality for kidneys was 3% to 11% (increasing with age); for livers
it was 4% to 37% (increasing with MELD score); for
hearts it was 6% to 22% (increasing with criticality status) . No mortality estimates provided for all
those who received

at

- risk organs. Of 2, 18 9 „high

- risk‟ donors, there was only one confirmed
cases of HIV
infection. Very

Low 0

- 1 0 0 0 0 0 0 Very Low Very Low145 Question 9: What is the impact of excluding potential solid organ donors with behavioral or nonbehavioral risk factors on th e organ donor pool? One study was included for this question. This study 200 was described in Question 8.

Question 10 : What is the impact of false positive tests on the organ donor pool? No studies were identified that met the inclusion criteria

.146 

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