Transplantation for Patients Infected with HIV: No longer Experimental but not yet routine (editorial)
The Journal of Infectious Diseases 2003;188:1405-1411
Jay A. Fishman
Infectious Disease Division, Massachusetts General Hospital, Boston, Massachusetts
“…….For HIV-infected individuals, the need for organ replacement has grown over time …….. End-stage liver disease (ESLD) is also increasing among HIV-infected persons, and does not appear to be reduced by HAART …….Recent studies, including that by Ragni et al. published in this issue of the Journal, have challenged the exclusion of HIV-infected persons as transplantation candidates ………..patients in this series had far-less-advanced liver disease at the time of transplantation than did the average national population undergoing this procedure……. most HIV-infected individuals, even those receiving effective HAART and, in particular, those coinfected with HCV, will not survive to receive a liver transplant, according to current listing criteria …..The series of individuals studied by Ragni et al. should provide an impetus to such investigation …..additional larger, multicenter, prospective trials must be performed to study liver transplantation among HIV-infected individuals with or without HCV infection ……If HCV-HIV coinfected individuals do as well (or do as poorly) after liver transplantation as does the general population, then restrictions on such transplantation should be lifted……It must be noted that HIV-infected patients with liver failure may only tolerate HAART if they receive liver transplants…..”
The first successful solid-organ transplantations were performed in 1954, just 50 years ago. The first descriptions of acquired immunodeficiency syndrome (AIDS) are now >20 years old. Over the years, the 2 fields of solid-organ transplantation and AIDS care have provided some of the greatest clinical and ethical challenges that the biomedical community has encountered . Until recently, human immunodeficiency virus (HIV) infection has been a contraindication for solid-organ transplantation, because of the inability to control viral replication in patients receiving exogenous immune suppression for the prevention of graft rejection . The advent of improved combination antiretroviral therapies (ARTs) has improved the survival of many HIV-infected individuals . One of the consequences of the prolonged survival of HIV-infected individuals has been the increasing impact of complications of common chronic illnesses. The impact of hypertension, chronic obstructive pulmonary disease, viral hepatitis, and diabetes is apparent in deaths due to liver, kidney, heart, and lung failure among patients who are HIV positive. Some of these diseases may be exacerbated by the side effects of antiretroviral therapy, which include hepatic dysfunction and altered lipid metabolism. However, as HIV replication is controlled and the incidence of opportunistic infection and malignancy declines, the approach to the long-term care of HIV-infected individuals with organ failure must be reassessed.
Recent studies [6-10], including that by Ragni et al.  published in this issue of the Journal, have challenged the exclusion of HIV-infected persons as transplantation candidates, by use of highly active antiretroviral therapies (HAARTs) to control HIV infection in individuals receiving liver and kidney transplants. The available data suggest that significant progress has been made but that hurdles remain before the full benefits of transplantation are experienced by individuals infected with HIV. In particular, individuals with liver failure who are intolerant of or unresponsive to ART may not benefit from transplantation. Patients coinfected with hepatitis C virus (HCV) and HIV may have accelerated progression of liver disease despite receiving HAART.
Thus, the challenge: given a desperate shortage of organs for transplantation, how do we select HIV-positive patients who will benefit from currently available approaches to AIDS therapy and organ replacement (i.e., how do we "do no harm")? What limitations, if any, should be placed on the deployment of such therapies? For HIV-infected persons, is organ transplantation "experimental" or merely an added complexity in the care of critically ill patients? What are the areas for future basic and clinical investigation?
Some background information is useful in the development of an approach to transplantation for patients with HIV/AIDS. In transplantation, improvements in immunosuppressive drugs, surgical techniques, and life-support technologies have resulted in previously unimagined successes for recipients of cadaveric liver transplants (3-year patient survival, 79.5%) and cadaveric kidney transplants (3-year graft survival, 78.5%), according to United Network for Organ Sharing/Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (data as of 1 August 2002) . The success of transplantation has stumbled in some areas, notably with regard to the toxicities of immunosuppressive agents and the somewhat primitive assays of allograft-specific immune function. Some technical issues, including the maintenance of vascular supply for tracheal and biliary anastomoses and the optimal techniques for transplantation involving live donors, remain problematic. The most challenging issues are the inadequate supply of organs for transplantation (>82,000 individuals are waiting for organs in the United States alone) and the lack of resources to support transplantation in developing regions. Recurrent disease (e.g., hepatitis C and IgA nephropathy), posttransplantation malignancies (e.g., lymphomas and skin cancers), and humoral (antibody-mediated) and chronic graft rejection remain major concerns.
HAART has resulted in improved survival and in immune reconstitution with reductions in AIDS-associated opportunistic infections . Unfortunately, not all patients respond to HAART, and some develop viral resistance after initiation of therapy. Many have intolerance of drugs and complications of therapy that require revised regimens. The effect of HAART on AIDS-associated malignancies remains heterogeneous . Perhaps the most challenging issue associated with HAART, similar to that associated with transplantation, is the lack of resources to support the deployment of HAART in developing regions.
THE NEED FOR TRANSPLANTATION AMONG PATIENTS WITH HIV/AIDS
For HIV-infected individuals, the need for organ replacement has grown over time. In the pre-HAART era, the incidence of renal and hepatic failure was greater in HIV-infected individuals than in the HIV-negative population. HIV-infected patients have a high incidence of renal dysfunction and are overrepresented in the population of individuals receiving dialysis . HIV-infected patients receiving dialysis have reduced survival, compared with uninfected patients undergoing dialysis; limited data suggest that HAART somewhat improves the survival of HIV-infected patients receiving dialysis . HIV infection is associated with a spectrum of renal diseases, with a disproportionate impact on black men and injection drug users (as reviewed in  and in ).
End-stage liver disease (ESLD) is also increasing among HIV-infected persons, and does not appear to be reduced by HAART [35, 36]. The risk factors for infection with HIV, HCV, or hepatitis B virus (HBV) are similarin particular, injection drug use (IDU) and the presence of hemophilia before the availability of viral assays (pre-1987). More than 90% of HIV-infected hemophiliacs and people with a history of IDU have HCV infection . The prevalence of coinfection with HIV and HCV is >25%, with higher rates occurring in areas where HCV or IDU is endemic and among hemophiliacs exposed to unscreened blood products; HIV-HBV coinfection is present in up to 10% of HIV-positive individuals [37, 4244]. HCV RNA levels increase in proportion to HIV load and declining CD4+ T lymphocyte counts [39, 45]. In the pre-HAART era, individuals with HCV-HIV coinfection, when compared with individuals with HIV infection alone, had more hepatic inflammation and cirrhosis (33% vs. 11%) and were more likely to have progression to ESLD [35, 36, 46, 47].
The mechanisms underlying the synergy between HCV and HIV remain unclear. This may reflect the direct effects of HIV on the pathogenesis of HCV infection (i.e., viral "cross-talk") and/or superimposed drug toxicity . HCV also appears to blunt the effect of HAART on T cell reconstitution , and HCV peptides may suppress T cell responses . Few data exist to predict the progression of HCV infection in patients receiving both effective HAART and currently available anti-HCV therapies. This remains an important area for investigation.
TRANSPLANTATION IN THE PRE-HAART ERA
Before HAART, organ transplantation for HIV-infected individuals was often disastrous. Early experience with transplantation fell into 2 categories: (1) transplantation performed for patients with known cases of AIDS, with the expectation that immune deficiency would obviate the need for exogenous immune suppression, and (2) accidental transmission of HIV with transplantation immune suppression without prior control of HIV replication. Individuals with AIDS who received organ transplants without exogenous immune suppression experienced acute graft rejection [2, 8, 51]. This was a consistent but surprising observation, given the marked T cell defects of AIDS. Accidental transmission of HIV to transplant recipients via organs or blood products, as well as immune suppression for transplantation in the pre-HAART era, was generally associated with an accelerated course of AIDS that included opportunistic infections and cancers [2, 8, 52-58].
As in the series of individuals studied by Ragni et al. , subjects who were intolerant of ART after transplantation and who had lower CD4+ lymphocyte counts and subjects with higher HIV loads tended to have poorer outcomes . In the pre-HAART era, HBV and HCV infections were predictors of poor outcomes. Of note, a small subset of patients receiving renal and hepatic allografts did not experience this accelerated course [8, 59-61]. The basis for this relative protection is uncertain but may include individuals with sustained responses to earlier antiretroviral therapies as well as individuals recognized as HIV-infected, "long-term nonprogressors." Even in a small series of liver transplant recipients who acquired HIV through perioperative blood transfusions or from HIV-infected organ donors, 5 of 8 patients survived 5 years, with only 1 patient developing AIDS .
HCV AND TRANSPLANTATION
The majority of HIV-infected individuals who require liver transplantation will be coinfected with HCV. HCV-HIV coinfection is a major hurdle to transplantation, because of rapid progression of HCV infection, intolerance of ART after transplantation, and clinical deterioration before transplantation (see the Organ Allocation section below) in this population .
Even among HIV-negative individuals, transplantation performed in the face of HCV infection remains unsatisfactory [63-65]. Reinfection with HCV is nearly universal after liver transplantation, although the clinical and biochemical manifestations of infection vary with viral genotype, response to therapy, immune responsiveness, and multiple undefined factors. In the absence of a vigorous CD4+ and CD8+ immune response (which is the rule in transplant recipients), progressive liver disease due to HCV commonly occurs. It is often impossible to distinguish HCV infection from graft rejection; patients often receive excess immune suppression that may exacerbate HCV (or HIV) infection. Although in some patients the response to therapy with interferon and ribavirin is prolonged suppression of HCV replication, many do not tolerate full doses of either agent because of the presence of hemolysis, leukopenia, systemic toxicity, anorexia, and neuropsychiatric complications. A subset of HCV-infected liver transplant recipients develops rapidly progressive HCV infection with bridging fibrosis, cirrhosis, and progressive liver failure. This is more common in subjects with HIV coinfection.
Unfortunately, the rate of death due to ESLD among HCV-HIV coinfected persons may be increasing despite the use of HAART . The use of antiretroviral protease and reverse-transcriptase inhibitors for the treatment of HIV infection in individuals with HCV infection often results in abnormal liver-function test results and increased plasma HCV RNA loads for the first 34 months of therapy. These results may be exacerbated in patients receiving immune suppression for organ transplantation. Recurrence of HCV infection appears to be more rapid in recipients of split cadaveric and live-donor organs, which may limit the use of reduced-size (i.e., live-donor) transplants for HCV-induced liver failure. The care of renal transplant recipients infected with HCV is also complicated by the limitations of current therapy: interferon- may provoke graft rejection, whereas ribavirin often precipitates hemolysis.
DRUG TOXICITY AND TRANSPLANTATION
Even outside the HCV-infected population, drug toxicity is a significant limitation to the use of HAART with immune suppression for transplantation [2, 35, 66]. For example, cyclosporine, tacrolimus and sirolimus, and the antiviral aspartyl protease inhibitors commonly used in HAART regimens are substrates, inhibitors, and/or inducers of liver cytochrome P-450 isoenzyme 3A4 (CYP3A4) hepatic enzymes and P-glycoprotein transporters of the gastrointestinal tract. Thus, the bioavailability and the blood and tissue levels of both antiviral agents and calcineurin inhibitors are altered in patients receiving these agents. Common adverse effects of these agentsin particular, biliary and hepatic toxicity, nephrotoxicity, hyperlipidemia, and hematopoietic toxicitymay be enhanced and may adversely affect a transplanted organ. In the series of individuals studied by Ragni et al. , pretransplantation intolerance of ART was experienced by 16.7% of subjects, but 80% of nonsurvivors did not tolerate HAART after transplantation .
The optimal combination of antiviral and immunosuppressive agents has not yet been determined. The clinical pharmacology is complicated by drug interactions, renal and hepatic dysfunction after transplantation, and the lack of direct measures of immune function relevant to graft survival (i.e., too little or too much immune suppression). Certain combinations of agents appear to be beneficial, whereas others are detrimental (as reviewed in [2, 6]). Use of antilymphocyte antibodies for induction of immune suppression and treatment of graft rejection has been associated with exacerbation of HIV replication.
The need for improved regimens of combinations of drugs for HAART and immune suppression is emphasized by the high incidence of graft rejection noted in the series of individuals studied by Ragni et al. . The majority of patients who were receiving liver transplants were treated for acute graft rejection, which is a major stimulus to the activation and replication of both HIV and HCV and which may precipitate graft loss due to HCV or late rejection. Improved approaches to immune suppression are needed for liver allografts infected by HCV.
The supply of organs for transplantation is woefully inadequate. This deficit has been the impetus for live-donor transplantation of kidneys, livers, and lungs and for development of nonhuman sources of organs for xenotransplantation. The rules governing the allocation of organs vary by organ. However, each individual without a living transplant donor is placed on a waiting list to receive organs from a deceased donor, with points awarded on the basis of disease severity, underlying comorbidities, and time spent waiting for organs. During the past decade, the number of patients waiting for liver transplantation has increased nearly 9-fold, from 2217 patients in 1992 to a peak of 18,505 patients in 2001.
The Model for End-Stage Liver Disease (MELD) score system was developed in 2002 to prioritize adult candidates for liver transplantation who are thought to have the highest mortality risk if they do not undergo transplantation . The MELD score is based on 3 biochemical variablesthe serum bilirubin level, the serum creatinine level, and the international normalized ratioand has been shown to be predictive of death 3 months after transplantation among patients with chronic liver disease. For patients without acute hepatic failure who have received liver transplants in the United States during the past year, the median MELD score at the time of transplantation was 22.16 (range, 1628) . In regions with severe organ shortages, transplantation may not occur until a MELD score of 2535 is achieved, which indicates severe organ failure, systemic illness, and/or hepatic malignancy.
In the series of individuals studied by Ragni et al. , the mean MELD score of survivors of liver transplantation was remarkably low (mean, 15; range, 733), compared with that of nonsurvivors (mean, 21; range, 1230). This finding suggests that the patients in this series had far-less-advanced liver disease at the time of transplantation than did the average national population undergoing this procedure. This may partially account for the excellent patient-survival rates observed. One of the truisms of transplantation is that "the less a patient needs a transplant, the better they do after transplantation." Critically ill patients do not tolerate the complex transplantation surgery well; healing is often delayed and metabolic parameters (largely, renal and hepatic function) are often disrupted by the effects of immune suppression. No MELD points are given for viral infection (with HIV, HCV, or HBV); these patients are often critically ill by the time appropriate organs become available.
In a recent study that reported on HIV-infected patients receiving HAART, 8 of 21 patients were placed on a waiting list for liver transplantation; the median MELD score at the time of listing was 16 (range, 830) . Only 1 of the 8 patients who were placed on a waiting list survived to transplantation, whereas 5 of the 8 patients died before receiving a liver. The patients who died had median MELD scores of 19 at evaluation and 27 two months before death. Like the patients from the series of individuals studied by Ragni et al. , the majority of these patients were coinfected with HCV (14 of 21 patients) or HBV (4 of 21 patients) . Thus, most HIV-infected individuals, even those receiving effective HAART and, in particular, those coinfected with HCV, will not survive to receive a liver transplant, according to current listing criteria. This finding suggests that the unexpected survival of the HIV-infected patients included in this series may have been due, in part, to the lower mean MELD score at the time of liver transplantation (i.e., the patients were less sick), the relatively short follow-up (mean, only 17 months), and the advantage conferred by the excellent patient-survival record for transplantation at each of the participating institutions.
TRANSPLANTATION IN THE ERA OF HAART
With HAART, renal and hepatic transplantation have become feasible for HIV-infected persons [2, 7, 69, 70]. However, HAART is not a magic bullet. Viral suppression is not universal. Many of the opportunistic infections normally controlled by T cell immune function are common to both patients with AIDS and transplantation patients. These opportunistic infections include infections due to Pneumocystis, cytomegalovirus, Candida species, and mycobacteria (both Mycobacterium tuberculosis and M. avium complex). Less common manifestations also occur in both patient groups; they include B cell lymphoma, progressive multifocal leukoencephalopathy, skin cancers, and toxoplasmosis. HAART will provide little protection against the occurrence of these manifestations in individuals with AIDS who receive exogenous immune suppression for transplantation. Patients who carry latent infections will require lifelong prophylaxis that would have been unnecessary without exogenous immune suppression.
The full impact of HAART on the evolution of ESLD and end-stage renal disease is not yet known. The number of HIV-infected individuals receiving organ transplants remains small. The available data confirm another truism: "Livers are not kidneys." HIV-infected patients tolerate full HAART therapies more often after renal transplantation than after liver transplantation. Thus, it is reasonable to consider kidney and, possibly, pancreas "transplantation in patients with HIV infection as analogous to transplantation in patients with other chronic illnesses" [71, p. 284]. Even so, kidney transplantation patients who are intolerant of ART may not receive the same benefits as does the general population of kidney recipients. Furthermore, for the HCV-HIVcoinfected patient after renal transplantation, the risk of HCV-mediated renal injury and/or graft rejection during receipt of interferon therapy remains substantial.
By contrast with kidney transplantation, liver replacement is not universally beneficial. In the series of individuals studied by Ragni et al. , individuals who are intolerant of or have experienced failure of ART (in general, patients with hepatitis C) do not experience the same survival benefit as do individuals with other underlying diseases. As noted by these authors, the small size of the subgroups precludes more meaningful analysis. The progression of HCV-mediated cirrhosis and hepatic failure in such patients is often rapid and may not be reduced by HAART. In fact, it appears that most HIV-HCV coinfected patients will not survive to transplantation, given current listing criteria. By the time that transplantation is performed, hepatic dysfunction has progressed, hepatorenal syndrome may occur, and intolerance of HAART and anti-HCV therapies is common. This subgroup of patients is expected to do less well than the average liver recipient and may not benefit from transplantation.
It must be noted that HIV-infected patients with liver failure may only tolerate HAART if they receive liver transplants. Far from discouraging such transplantations, additional larger, multicenter, prospective trials must be performed to study liver transplantation among HIV-infected individuals with or without HCV infection. These must be performed with standardized approaches to immune suppression, treatment of graft rejection, and anti-HCV and HAART therapies. The series of individuals studied by Ragni et al.  should provide an impetus to such investigation. Certainly, this series suggests the characteristics of HIV-positive recipients who may benefit most from transplantation: (1) patients without HCV coinfection or in whom HCV infection is well controlled and (2) patients tolerating HAART (or "long-term nonprogressors") with undetectable HIV loads and immune reconstitution. If HCV-HIV coinfected individuals do as well (or do as poorly) after liver transplantation as does the general population, then restrictions on such transplantation should be lifted.
Not all centers will be capable of performing organ transplantation for HIV-infected persons. Management of transplant recipients and HIV infection requires expertise to manage posttransplantation drug toxicities, technical problems, and medical complications. A carefully coordinated and dedicated team that includes transplant surgeons, transplant infectious disease clinicians, experienced HIV clinicians, nephrologists, hepatologists, and immunologists must be available for routine patient care. AIDS and organ transplantation require lifelong commitments by the patient and by the medical team. No center without such expertise should take on the care of HIV-infected transplant recipients. Although the impacts of the diseases are different, it should be noted that the risk for transmission of HBV infection by needlestick injury is greater (10-fold greater) than that for HCV infection, which is greater (10-fold greater) than that for HIV infection. Although "universal precautions" are used to minimize the risks inherent to the care of critically ill patients, the risks to surgeons, physicians, and other medical personnel are not irrelevant and must be considered in the development of policy for this field .
WHERE DO WE GO FROM HERE?
Larger series are needed to study the effects of pretransplantation listing criteria, renal function, ART regimens, HIV loads, and other comorbidities; longer posttransplantation follow-up data are also needed. Further studies of the interactions between HIV and HCV in the pathogenesis of liver failure are essential. New models (in vitro and animal models) are needed to assess viral interactions and novel therapies. Data on HIV-positive individuals requiring pancreas, heart, or lung transplantation are needed. Novel approaches to the care of HIV-infected individuals may emerge from transplantation, including (1) combined hematopoietic stem cell transplantation and solid-organ transplantation to induce immunologic "tolerance" (donor-specific immune unresponsiveness) or (2) xenotransplantation (organs from other species that may be resistant to infection with HIV and other viruses).
Hepatitis B virus (HBV) infection was, until recently, a relative contraindication to liver transplantation. Relapse after transplantation was common and progression to graft failure inevitable. Control of HBV by antiviral agents and antibody therapy has allowed individuals with HBV to undergo transplantation routinely at most centers. Control of HIV and HCV infections is not yet routine. Defects in the control of infection in the face of immune suppression remain an Achilles' heel of transplantation. It is time for us to help those we can and to redouble our efforts for those we cannot.
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