Transmission of human immunodeficiency virus and hepatitis C virus through liver transplantation

Authors


  • See Editorial on Page 1564

Abstract

In November 2007, a liver transplant recipient was confirmed to have human immunodeficiency virus (HIV) and hepatitis C (HCV) infection after the organ procurement agency notified our institution that the donor has been HIV and HCV positive. We reviewed medical records and the collected blood sample results for HIV and HCV testing. A 66 year old female with nonalcoholic steatohepatitis cirrhosis underwent liver transplantation. The donor was a male who had sex with men who received multiple blood transfusions during resuscitation. Preoperative testing for HIV and HCV antibodies were negative for both donor and recipient. Ten months later, HIV and HCV were identified with nucleic acid testing in the recipient and in the stored donor sera. This is the first reported case of HIV transmission from solid organ transplantation in 20 years, and the first ever reported case of simultaneously transmitted HIV and HCV. The current case represents a high risk donor with newly-acquired HIV and HCV who transmitted the diseases during the window period of the infections. In this era of organ shortages one option would be avoidance of any high-risk donor organs. Another option would be to continue the use of such organs with appropriate informed consent, acknowledging the limitations of current screening tests for HIV and HCV. This report should serve as a wake-up call to the transplant community to consider revamping organ donor screening for HIV and HCV using nucleic acid testing as well as reconsidering the ongoing use of high-risk donors. Liver Transpl 14:1603–1608, 2008. © 2008 AASLD.

The transmission of human immunodeficiency virus (HIV) through solid organ transplantation is extremely rare. The last documented case occurred in 1987.1 We present a case of HIV and hepatitis C virus (HCV) infection transmitted through the transplantation of an infected liver graft.

CASE REPORT

Because of the sensitive nature of this case, some recipient demographics have been omitted. A 66-year-old female with diabetes and obesity presented with cirrhosis, ascites, and hepatic encephalopathy. There was no history of alcohol use, intravenous drug use, blood transfusions, or tattoos. Testing for viral hepatitis, autoimmune hepatitis, biliary cirrhosis, and hereditary liver diseases was negative. An HCV antibody test with the Ortho HCV version 3.0 enzyme-linked immunosorbent assay (Ortho-Clinical Diagnostics, Raritan, NJ), an HCV-RNA test with the Abbott real-time HCV assay (Abbott Molecular, Inc., Des Plaines, IL), and an HIV antibody test with the HIV-1/HIV-2 recombinant DNA enzyme immunoassay (EIA; Abbott Laboratories, Abbott Park, IL) were negative in November 2006. The patient was listed for orthotopic liver transplantation (OLT) and required repeat hospitalizations for hepatic encephalopathy while awaiting OLT. Her last pre-OLT Model for End-Stage Liver Disease score was 19.

A donor liver was offered in January 2007 from a 39-year-old male who had sustained head trauma. He had received multiple transfusions during resuscitation. The donor's risk assessment questionnaire was answered by a close family friend. The donor had no known history of hemophilia, viral hepatitis, HIV, prior transfusions, tattoos, intravenous drug use, or incarcerations. He was a male who had sex with men. He had previously tested negative for HIV. As part of predonation testing, both pretransfusion and posttransfusion blood samples were tested for HCV antibody with Abbott HCV EIA 2.0 (Abbott Laboratories) and for HIV antibody with HIV-1/HIV-2 recombinant DNA EIA (Abbott Laboratories) and found to be negative. A biopsy of the donor liver revealed mild steatosis.

The transplant surgeon accepted the donor liver. The donor heart and kidneys were accepted by other institutions in Chicago, IL. Informed consent was obtained with a standard consent form from the recipient's son as the patient was encephalopathic. The patient underwent OLT, and the explant revealed nonalcoholic steatohepatitis with cirrhosis. No induction therapy with thymoglobulin or OKT3 was used. The patient was discharged on tacrolimus and corticosteroids on postoperative day 8. The postoperative course was complicated by intermittently elevated liver enzymes, and multiple liver biopsies suggested acute rejection and subsequent biliary obstruction requiring therapeutic endoscopic retrograde cholangiopancreatography and a surgical bile duct revision. No findings were seen to suggest an obvious diagnosis of HCV or HIV.

In November 2007, the local organ procurement organization (OPO) notified our institution of the possibility that the donor of the liver graft had been HIV-positive and HCV-positive. Our institution was not provided with the specific details that led to the follow-up testing, but later we learned from media reports that the heart and kidney recipients from the same donor (at other institutions in Chicago, IL) had become HIV-positive and HCV-positive by nucleic acid testing (NAT). For this reason, our patient was tested for HIV and HCV. HCV antibody was negative, but HCV-RNA with the Abbott real-time HCV assay (Abbott Molecular) was greater than 5,000,000 IU/mL. HIV-1 antibody was positive with HIV-RNA greater than 500,000 copies/mL by the Versant HIV-1 RNA 3.0 branched DNA assay (Bayer Diagnostics, Norwood, MA). The CD4 count was 34 cells/mm3. The patient and her family were informed of the diagnoses by the transplant surgeons in their outpatient clinic. As expected, the patient and her family were quite distraught. The patient became very depressed, and this condition subsequently worsened over the remainder of her clinical course. She was referred to the infectious disease clinic for evaluation and management of her HIV.

Despite the low CD4 count, there were no overt manifestations of acquired immune deficiency syndrome at the time of diagnosis. The patient was started on highly active antiretroviral therapy (HAART) with efavirenz, emtriva, and tenofovir. She was also started on prophylaxis with sulfamethoxazole and trimethoprim, valganciclovir, and azithromycin. Tacrolimus doses were decreased after the initiation of HAART and were adjusted to standard levels. The CD4 count increased to 112 cells/mm3 5 weeks later. However, HAART was subsequently held because of the patient's clinical deterioration with development of urosepsis, cytomegalovirus viremia, and acute renal failure. Extensive workup including endoscopic retrograde cholangiopancreatography, liver biopsy, and computed tomography scans of the entire body were most significant for multiple ring-enhancing lesions in the brain and subdural hematomas. Despite aggressive therapy, the patient expired at the end of January 2008 (1 year post-OLT).

Abbreviations

CDC, Centers for Disease Control; CMV, cytomegalovirus; EIA, enzyme immunoassay; FHF, fulminant hepatic failure; HAART, highly active antiretroviral therapy; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HTLV-III, human T-lymphotropic virus type III; NAT, nucleic acid testing; OLT, orthotopic liver transplantation; OPO, organ procurement organization.

DISCUSSION

Transmission of HIV through solid organ transplantation is extremely rare, with only sporadic case reports published1–8 (see Table 1). Most cases involved kidney transplants prior to 1985, when HIV antibody donor screening was implemented by the Public Health Service.9 The last reported case occurred in 1987.1 Since that time, more than 420,000 organ transplants have been performed in the United States.10 We report the first case of HIV transmitted by solid organ transplant in 20 years and the first case ever reported of simultaneous HIV and HCV transmission.

Table 1. Cases of HIV Transmission Through Solid Organ Transplantation
ReferenceYear of OccurrenceYear of ReportOrgan TransplantedDonor Risk FactorDonor HIV statusRecipient DemographicsRecipient Outcome
  1. Abbreviations: CMV, cytomegalovirus; EIA, enzyme immunoassay; FHF, fulminant hepatic failure; HIV, human immunodeficiency virus; HTLV-III, human T-lymphotropic virus type III.

119871989Kidney (living-related)Homosexual maleNegative EIA antibody 8 months prior to donation. Found to be HIV antibody positive on postdonation testing.26-year-old maleDeveloped a mononucleosis-like infection 7 days post-transplant. HIV seroconversion 57 days post-transplant.
219861988LiverUnknownPositive EIA antibody test, but test results were not waited for because of FHF in recipient.16-year-old maleHIV antibodies found 3 days post-transplant. Developed acute HIV infection syndrome and aplastic anemia. Died 49 days post-transplant
319851992HeartUnknownNegative by 2 separate EIA antibody tests. Retrospective testing of donor splenic tissue confirmed HIV.55-year-old maleHIV antibodies positive by EIA (but negative on western blot) found 8 months post-transplant. Had developed herpes zoster, thrush, Pneumocystis carinii pneumonia, CMV retinitis, and cerebritis. Died 10 months post-transplant. Subsequent testing on stored donor serum revealed positive HIV-1 p24 antigen.
319851992LiverUnknownNegative by 2 separate EIA antibody tests. Retrospective testing of donor splenic tissue confirmed HIV.26-year-old maleDied from hepatic and renal failure 24 days post-transplant. Retrospective testing of stored sera showed positive HIV-1 p24 antigen.
319851992KidneyUnknownNegative by 2 separate EIA antibody tests. Retrospective testing of donor splenic tissue confirmed HIV.45-year-old maleFound to be HIV-positive at 17 months post-transplant during a dementia workup. Died 32 months post-transplant.
319851992KidneyUnknownNegative by 2 separate EIA antibody tests. Retrospective testing of donor splenic tissue confirmed HIV.34-year-old maleFound to be HIV-positive 7 months post-transplant. Had already lost the transplanted kidney and was back on dialysis. Died because of complications of cardiomyopathy, pancreatitis, and renal failure 14 months post-transplant.
419861987HeartMultiple blood transfusions (>50) prior to deathInitial antibody testing negative. Found to be positive on postdonation testing.Age and gender not reportedExpired in the operating room.
419861987LiverMultiple blood transfusions (>50) prior to deathInitial antibody testing negative. Found to be positive on postdonation testing.Age not reported, maleFound to be HIV-positive at 3 months post-transplant. No HIV-related complications reported.
419861987KidneyMultiple blood transfusions (>50) prior to deathInitial antibody testing negative. Found to be positive on postdonation testing.Age not reported, maleFound to be HIV-positive at 2.5 months post-transplant. No HIV-related complications reported.
519841985KidneyHemophiliaUnknown42-year-old maleHTLV-III antibodies were found 15 months post-transplant during a workup for malaise, fever, and rash.
519841985KidneyHemophiliaUnknown52-year-old maleHTLV-III antibodies were found 16 months post-transplant. Patient was tested because of the positive diagnosis in the other kidney recipient.
619831987KidneyUnknownPositive on retrospective testing.51-year-old maleDied from pneumonia 16 days post-transplant. No serum available for testing.
619831987KidneyUnknownPositive on retrospective testing.38-year-old maleHIV antibodies were detected at 50 days post-transplant. Patient had been tested because of fever, leukopenia, thrombocytopenia, and adenopathy.
619841987KidneyIntravenous drug useUnknown28-year-old maleHIV antibodies were detected 56 days post-transplant. Patient had been tested because of fever, leukopenia, thrombocytopenia, and acute splenomegaly.
719841985KidneyIntravenous drug useUnknown28-year-old maleFever and leukopenia occurred at 2 to 7 weeks post-transplant. HTLV-III antibodies were detected at 8 months post-transplant.
719841985KidneyIntravenous drug useUnknown48-year-old femaleFever and leukopenia occurred at 2 to 7 weeks post-transplant. HTLV-III antibodies were detected at 8 months post-transplant.
719841985KidneyIntravenous drug useUnknown31-year-old femaleFever and leukopenia occurred at 2 to 7 weeks post-transplant. HTLV-III antibodies were detected at 8 months post-transplant.
719841985KidneyIntravenous drug useUnknown39-year-old maleFever and leukopenia occurred at 2 to 7 weeks post-transplant. HTLV-III antibodies were detected at 8 months post-transplant.
719841985KidneyIntravenous drug useUnknown40-year-old femaleHTLV-III antibodies were detected at 8 months post-transplant. Clinical course not recorded.
819821987Kidney (living-related)Homosexual malePositive on retrospective testing.38-year-old femalePatient developed fevers, anorexia, Pneumocystis carinii pneumonia, histoplasmosis, and Kaposi's sarcoma. The patient died 10 months post-transplant. HIV antibodies were noted on retrospective testing.

Several potential mechanisms exist for the transmission of HIV through organ transplantation, as shown in Table 1. These include testing of donors in the window period between the time of exposure and the development of a positive HIV antibody, dilution of the donor's serum by extensive transfusions, inappropriate timing of pretransplant HIV testing (in the case of living-related transplant), inability to await the HIV test results, and false-negative HIV antibody tests. The time period from HIV exposure to the development of HIV antibodies is approximately 22 days, but it can range up to 6 months.11, 12 By standard antibody testing, the patients are HIV-negative, but they are still potentially infectious. The use of individual donor NAT allows the detection of HIV infection prior to antibody seroconversion, reducing this window period by approximately 50% to 75%.13, 14

In 1994, the Centers for Disease Control (CDC) issued guidelines addressing donor screening, testing, and exclusion, as well as recipient testing, for prevention of HIV transmission through organ transplantation.15 Table 2 lists the suggested donor exclusion criteria. Based on the available data, the guidelines did not recommend the use of p24 antigen testing or NAT for HIV-RNA. The guidelines did note that these donors could be considered if “the risk to the recipient of not performing the transplant is deemed to be greater than the risk of HIV transmission and disease.” In those cases, informed consent was deemed essential. Posttransplant testing of all solid organ recipients of high-risk donors for HIV was suggested but not mandated.

Table 2. Suggested Donor Exclusion Criteria
Laboratory and Medical Exclusionary Criteria
  1. Abbreviation: HIV, human immunodeficiency virus.

Positive HIV antibody
Inability to test a donor's HIV status
Worrisome signs or symptoms for the presence of HIV
Behavior/History Exclusionary Criteria
Men having sex with men in the preceding 5 years
Use of nonmedical injectable drugs in the preceding 5 years
Persons with clotting disorders who have received human-derived clotting factor concentrates
Persons engaging in sex in exchange for money or drugs in the preceding 5 years
Persons having sex with any person described above or with a high-risk or known/suspected HIV-positive partner in the last year
Persons exposed to known or suspected HIV-infected blood within the last year
Inmates of correctional facilities

HCV transmission through transplantation has also been described. The New England Organ Bank in 1991 identified 29 recipients (19 kidneys, 6 hearts, and 4 livers) of HCV-positive donor organs.16 Non-A–non-B hepatitis developed in 48% of the recipients, with HCV confirmed in 92% of those cases. Similar to HIV transmission, HCV transmission through transplantation has also been documented during the 8- to 10-week HCV window period.17 The conclusion from these studies and from a CDC review was that NAT would have detected the HCV infection prior to the transplants.18

The process of organ acquisition involves notification of the local OPO of potential donor organs. They complete a risk assessment questionnaire to identify high-risk donors as outlined in Table 2 according to the CDC guidelines.15 The OPO performs standard serologic testing, including pretransfusion and posttransfusion testing for blood typing, HIV-1/HIV-2 antibodies by EIA, HCV antibody by EIA, hepatitis B surface antigen and hepatitis B core antibody, cytomegalovirus antibody, and Epstein-Barr virus antibody as well as rapid plasma reagin screening. A plasma dilution worksheet is also completed to identify donors at increased risk of false-negative testing from hemodilution. Current serologic testing does not include NAT. The donor evaluation and risk assessment results are then provided to the transplant center. The transplant surgeon has the option of accepting or refusing the organ. If it is accepted, the recipient is informed of the potential high-risk status of the donor. The recipient then has the option to accept or decline the offer.

In light of this report, one solution would be avoiding the use of any high-risk organs. However, with more than 16,000 current OLT candidates on the waiting list,10 a relatively constant number of OLTs being performed annually, and a substantial rate of waiting-list deaths, this may not be the most appropriate choice. The dilemma of using high-risk donor organs requires the transplant center to balance the risk of further hepatic decompensation and death of the recipient versus the very small but real risk of the transmission of infectious diseases. The potential recipient's status needs to be evaluated with surrogate markers such as the Model for End-Stage Liver Disease score and overall functional status. Each center should have its own policies and procedures in place to deal with such donor organ offers. Although it is controversial, many centers, including our own, consider high-risk and other extended criteria donors for their OLT recipients. This is especially true in cities and regions with intense competition for donor organs, as illustrated in this case in which 3 separate transplant centers used organs from this high-risk donor. Since the development of this case, our center has instituted the use of a specific consent form to be used in cases of high-risk donors. The patient and his or her family must understand the potential consequences of using such an organ as well as the potential consequences of declining the organ and remaining on the waiting list.

An alternative solution would be the implementation of NAT as a prerequisite to organ donation. However, many variables, such as a delay in organ utilization and an increase in costs, must be considered. Using our hospital laboratory as a reference, we found that the most rapid turnaround time for HIV antibody is 1 hour with the OraQuick Advance HIV-1/2 antibody test (Orasure Technologies, Bethlehem, PA). The turnaround time is 24 hours for HIV-RNA NAT, 4 hours for HCV antibody, and 24 hours for HCV-RNA NAT. Given these turnaround times, the additional delay of waiting for NAT would be impractical as donor organs show deterioration of function with increasing ischemic times, which translates into overall inferior graft and recipient outcomes. The incremental cost associated with NAT would also be considerably higher.

As an example of a technique for decreasing infectious disease transmission, pooled NAT was implemented for screening blood donations in 1999 for HIV and HCV. While successfully decreasing the risk of transmission of both viruses, NAT does not completely eliminate the risk because donor testing can still occur during the window period.19–23 NAT for blood donations is estimated to prevent 5 cases of HIV transmission and 56 cases of HCV transmission annually at an estimated cost of more than $100 million annually, or $1.5 to 4.3 million per quality-adjusted year of life.24, 25

If and when similar cases of HIV transmission through solid organ transplantation occur in the future, our recommendation would be an honest and forthright approach in relaying the information. One should explain how such an event could have occurred and how the current screening tests are imperfect and limited. Each transplant center will need to individualize the approach on the basis of its relationship with the patient, but incorporating the support of social workers, psychologists/psychiatrists, and even clergy may be appropriate. An infectious disease specialist should be consulted to help manage the patient appropriately. Also, providing positive feedback on the improved outcomes of HIV patients in the era of HAART and in the setting of OLT, including the existence of a National Institutes of Health–supported multicenter HIV OLT study, may be beneficial to the patient.26–30

In conclusion, we present the first reported case of HIV transmission from solid organ transplantation in 20 years and the first ever reported case of simultaneously transmitted HIV and HCV. These infections were undetected by current screening tests because both infections were present in their respective window periods in a high-risk donor. In this era of organ shortages, each transplant center will need to weigh the risk-benefit ratio of using high-risk donor organs. One option would be avoidance of any high-risk donor organs. Another option would be to consider the use of such organs. However, the recipient must be informed of the limitations of the current testing methods in identifying donors with potential HIV and HCV in the window period, prior to giving consent. The current NAT turnaround time is too slow for practical use, and prevention of future cases will require the development of more rapid NAT but at a high cost with a low yield. Ultimately, this report should serve as a wake-up call to our transplant community to consider revamping donor screening for HIV and HCV using NAT and to reevaluate the ongoing use of high-risk donors for OLT.

Ancillary