HIV infection and liver transplantation: A review of the literature

The history of human immunodeficiency virus (HIV) disease to date can be divided into two distinct eras: pre-HAART (pre-1996) and post-HAART (post-1996). HAART, or highly active antiretroviral therapy, refers to the use of combination antiretroviral therapy to suppress HIV viral replication, thereby enabling immune reconstitution. It is now well documented that HAART has resulted in dramatic improvements in HIV-related morbidity and mortality, and that it radically alters the natural history of HIV disease.[1-3]

While the use of HAART has largely transformed HIV disease into a chronic, manageable illness,[1] most antiretroviral agents are metabolized through the liver, and can cause varying degrees of hepatotoxicity.[4,5]

In addition, viral coinfection with either hepatitis B or hepatitis C has become a leading cause of morbidity and mortality among people living with HIV.[6-8] HIV and hepatitis C virus (HCV) coinfection is an important problem in British Columbia. Up to 90% of HIV-infected injection drug users are HCV-positive,[9] and over 40% of individuals receiving antiretrovirals who have been tested for hepatitis C in the province are coinfected.[10] Already, hepatitis C is an independent predictor of mortality among HIV-positive individuals receiving antiretroviral treatment in British Columbia.[10] The prevalence of chronic hepatitis B infection among HIV-infected individuals in North America is estimated at 9% and is also an important source of morbidity among HIV-infected persons.[6] Therefore, although the prognosis for HIV-infected patients has improved remarkably over the past several years, it is the presence of coexisting morbidities, including end-stage liver disease secondary to viral hepatitis, which is now having the greatest impact on survival.[6,11,12]

These issues have all contributed to an increasing demand for access to orthotopic liver transplants (OLT) by HIV-positive individuals and their health care providers. This paper provides a review of the literature to date on the rapidly changing state-of-the-art in HIV and transplantation.

HIV and transplantation pre-HAART

HIV infection has until recently been considered an absolute contraindication to transplantation.[13,14] Historically, excluding HIV-infected individuals with end-stage organ disease was based primarily on the concept that the immune suppression required for organ transplantation would exacerbate an already immunocompromised state. Indeed, several reports from the pre-HAART era of individuals who were either infected with HIV at the time of the transplant (perioperatively) or retrospectively found to have HIV, suggested that progression to AIDS in these individuals was extremely rapid.[7,15,16] However, there were also reports in the literature of HIV-infected individuals in the pre-HAART era who received transplants, survived, and maintained normal graft function for years following the transplant.[15,17-20] Progression of HIV disease was the most common cause of death in HIV-positive transplant recipients during this pre-HAART period.

HIV and transplantation post-HAART

Since 1996 and the advent of HAART, the situation has changed substantially for HIV-positive individuals requiring transplantation. Reports from the United States,[7,21,22] the United Kingdom,[23,24] Sweden,[25] Japan, and France[27] all suggest that liver (and kidney) transplantation is a viable option, in terms of both patient and graft survival for people living with HIV/AIDS. The published reports of these transplants are summarized in Table 1, while Table 2 describes patient and graft survival in a large cohort of HIV-negative transplant recipients, using data from the United Network of Organ Sharing (UNOS) database.

Among the HIV-positive individuals, there is variability in terms of survival rates and other outcomes. The variability is due to a number of factors. Many of the patients also have or had hemophilia; some were treated for hepatitis C while some were not; some were treated with Rebetron (standard formulation of ribavirin and interferon alfa-2b), while some were treated with the more efficacious pegylatedinterferon; patients were immunosuppressed with a variety of agents. Some had histories of AIDS-defining illnesses, while others did not. In general, however, the data suggest that liver transplantation offers a viable intervention for people with end-stage liver disease who are also HIV-positive.

Hepatitis C coinfection

Hepatitis C is the leading indication for orthotopic liver transplants in the United States and elsewhere.[28-32] Although controversial, a large study of the UNOS database found an increased hazard of death, with a hazard ratio of 1.23 (95% confidence interval [CI], 1.12-1.35) among those infected with hepatitis C, and that this probability increased to 1.56 (95% CI, 1.35-1.81) among women with hepatitis C.[33] Consistent with these data, hepatitis C does appear to be one of the contributing factors of complications and death among the HIV-infected individuals to have been transplanted in the post-HAART era.

Exogenous immune suppression

The literature indicates a number of important postsurgery issues specific to HIV-infected patients. These include antiretroviral management and the prevention of drug interactions with immunosuppressants. There are several references in the literature to positive and negative interactions between exogenous immunosuppressants and antiretrovirals, specifically tacrolimus.[36,37] The required amount of exogenous immune suppression in HIV-positive OLT recipients is unknown, but believed to be similar to non-HIV-infected transplantation recipients.[7] Cyclosporine may actually have a particularly beneficial impact as an immunosuppressant for HIV-positive individuals undergoing transplantation as it is believed that cyclosporine may interfere with the primary target and receptors of HIV.[38]

HIV and the ethics of transplantation

There are a number of ethical issues surrounding the question of HIV-positive transplant recipients. Transplantable organs are scarce, and therefore determining the most ethical system of allocation requires simultaneous consideration of efficacy, urgency, and equity. The number of HIV-infected patients to have received transplants is still small enough that a direct comparison of efficacy is not yet possible. However, preliminary data do suggest that the rate of favorable outcomes between HIV-positive and HIV-negative are not dissimilar.[38] Even if HIV-positive individuals have somewhat poorer outcomes, relative efficacy should not be the sole ethical criterion for determining eligibility. Patients with HCV[28] or diabetes,[39] and older patients,[30] women,[28] and African-American and Asian patients[39] have more post-transplantation complications and diminished survival. These patient groups are nonetheless eligible for transplantation, as are patients who require re-transplantation, even though the probability of survival in these individuals is reduced.

Medical urgency is the primary criterion for determining patient eligibility in the United Network of Organ Sharing,[40] and their policy regarding HIV/AIDS states clearly that HIV-seropositivity should not automatically exclude individuals from receiving a transplant.[40]

Intraoperative viral transmission

Despite universal precautions, viral transmission may occur during surgery. The Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis indicates that the risk of transmission of HIV is low (0.3%, 95% CI: 0.2% – 0.5%), and is substantially lower than the risk of transmission of hepatitis C (1.8%, range 0% – 7%).[41] Fortunately, there is effective postexposure prophylaxis to prevent occupational HIV transmission. The efficacy of postexposure prophylaxis for the prevention of occupational hepatitis C transmission has yet to be firmly established.

Policy: HIV and transplantation in British Columbia

The British Columbia Transplant Society (BCTS) has adopted a policy regarding HIV and transplantation, the first such policy in Canada. In order to be placed on the waiting list for a transplant, HIV-positive candidates must first fulfill all criteria required of HIV-negative individuals and then have a CD4 count greater than 150 cells/mm3, an undetectable HIV viral load, and be on antiretroviral medication both at the time of being wait-listed, and at the time of transplantation (correspondence with Dr Eric Yoshida, medical director of the Liver Transplant Program, the BC Transplant Society, 17 July 2003). While antiretroviral therapy is critical in the post-transplantation management of HIV-positive recipients, its utility prior to transplantation, particularly in the context of advanced liver disease, has not been established.[38] At this time, an HIV-positive person has not received a transplant in British Columbia or been placed on the waiting list.

Summary

Although there are many questions that need to be addressed, there is now sufficient evidence to indicate that HIV-positive individuals who respond to highly active antiretroviral therapy can be successful recipients of orthotopic liver transplants. Considering HIV as an absolute contraindication to transplantation is a historical artifact, and a practice not based on current medical evidence. When it comes to ethical concerns, HIV is now considered on a par with other chronic illnesses, such as hepatitis C monoinfection, diabetes, or hemophilia.

There are, however, factors that will more likely result in successful transplantation in HIV-positive patients. A key factor is the ability to suppress HIV replication using combination antiretroviral medication post-transplantation. Another key factor is the existence of a multidisciplinary team of health care providers. In addition to hepatologists, this team must include clinical immunologists, transplantation surgeons, a knowledgeable pharmacist, and an HIV specialist. Strong psychosocial support must also be available.

“All published reports of transplantation in HIV-positive patients who are receiving multidrug antiretroviral regimens have concluded that, in most cases, HIV infection does not affect the outcome of the transplantation.”[42]

Competing interests
None declared.

 Table 1. HIV-positive orthotopic liver transplant recipient outcomes.

Table 2. HIV-negative orthotopic liver transplant recipient outcomes.

Paula Braitstein, MA, MSc

Ms Braitstein is a PhD candidate at the University of British Columbia and a research associate at the British Columbia Centre for Excellence in HIV/AIDS.