For patients with end-stage liver and kidney disease—not to mention patients with end-stage lung and heart disease—transplantation may be the only option. According to the American Council on Transplantation, more than 50,000 people benefit from organ transplantation every year. The United Network for Organ Sharing (UNOS) concurs and has always allowed HIV-positive patients to add their names to its organ waiting list (UNOS) still excludes potential donors known to be HIV-positive or perceived to be carriers of the virus [e.g., gay men, intravenous drug users, prostitutes, etc.]). However, many insurance companies and transplant centers balk at the idea of transplantation involving HIV-positive patients based on two factors.
First, before the advent of HAART, people with HIV infection had a shortened lifespan as a result of immune deficiency and the risk of life-threatening complications. Compounded by the facts that donors are rare and demand is high, transplant centers often consider projected survival in deciding who receives a coveted organ. A second concern has been that major surgery and the use of immunosuppressive drugs to prevent organ rejection may exacerbate an HIV-positive patient's immune deficiency, causing rapid disease progression and death.
Right off the bat, it's safe to say that HAART has significantly altered the natural history of HIV infection and that the projected lifespan of HIV-infected patients is, perhaps, on a par with that of other patients with chronic illnesses such as diabetes and hypertension. Thus, it can be strongly argued that exclusion of HIV-positive patients from transplantation based solely on the fear of shortened survival no longer holds water. What remain, however, are concerns regarding the efficacy of organ transplantation and the safety of immunosuppressive drugs in HIV-infected patients.
Drs. Michelle Roland, Peter Stock, and their colleagues at the University of California San Francisco (UCSF) recently received a substantial $2 million in State of California funding to evaluate transplant safety in a small number of HIV-positive people with end-stage kidney and liver disease. At the November 2000 meeting of PRN, Dr. Roland provided a litany of data regarding organ transplantation in the setting of HIV and introduced members to the groundbreaking and incredibly ambitious UCSF study now under way, along with the multisite study currently under development.
|Attitudes Toward Transplantation And Historical Experience
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As pessimistic as Dr. Spital's findings seem, Dr. Roland seemed much more positive. "We have 14 transplant centers throughout the United States who are enthusiastic about our transplant study at UCSF and are actively participating in the development of a multisite study, some of which are already performing such transplants. This really impressed us and I think it reflects a growing trend among surgeons and transplant centers. It's a matter of education, really. Transplant surgeons who are familiar with the progress made in recent years or who work with HIV specialists are much more open-minded. This interest in the transplant world is growing in leaps and bounds."
The greatest amount of experience with organ transplantation in HIV-infected people was in the pre-HAART era. While some of the initial reports demonstrated worse outcomes following transplantation in these patients, other reports have suggested that HIV-infection does not have adverse effects on graft survival. One report discussed by Dr. Roland came from the University of Minnesota and was published in 1991 (Erice, 1991). Data collected from five HIV-positive transplant recipients at the University of Minnesota were studied with data from 83 reported cases of HIV-infected organ recipients from other centers. Sixty-six of the 88 patients were HIV-negative before transplantation and received organs or transfusions of blood from individuals who were positive for HIV.
Twenty-five (28%) of the 88 patients developed AIDS, and 20 of the 25 (80%) died of AIDS-related complications approximately 37 months after transplantation. Another nine patients (10%) developed other HIV-related diseases. The mean time of progression to AIDS was 27.5 months among all patients with AIDS. For patients who were HIV-negative at the time of transplantation, the mean time of progression to AIDS was 32 months, whereas patients who were HIV-positive before transplantation developed AIDS within 17 months.
Transplant-specific data are also available from the University of Minnesota review. Among patients receiving a kidney transplant, 48 were infected with HIV in the perioperative period. Thirty-seven of these 48 kidney recipients reported graft function, and 76% of these had normal graft function. After a mean follow-up time of 35 months, 13/48 (27%) patients developed AIDS, 7 (15%) developed symptomatic HIV, and 28 (58%) were asymptomatic. There were 13 deaths during the follow-up time, 11 (85%) in people with AIDS. Of the 11 patients who received a kidney transplant and were HIV-positive at the time of surgery, eight reported graft function, 6 (75%) of which were normal. After a mean follow-up of 31 months, 3 (27%) patients progressed to AIDS and 8 (73%) remained asymptomatic. Among the four deaths reported, three occurred in people with AIDS.
As for liver recipients, 12 patients were HIV-negative at the time of transplantation. Eleven of the 12 (92%) patients had normal graft function. After 37 months, 3 (25%) developed AIDS, 2 (17%) developed symptomatic HIV, and 7 (58%) remained asymptomatic. Four deaths in this cluster were reported, two of which occurred in asymptomatic patients. The ten patients who were HIV-positive at the time of transplantation did worse-approximately 40% had AIDS 19 months post-transplantation and nine died approximately 14 months after the liver transplant. Five of the nine deaths were in asymptomatic patients and resulted from sepsis, aspiration, drug toxicity, or excessive blood loss during surgery.
Another report discussed by Dr. Roland was published in 1994, this time by an infectious disease team at the Hopital Bichat-Claude Bernard in Paris (Bouscarat, 1994). Eleven HIV-positive liver recipients were included in the report, all of whom acquired the infection between 1985 and 1987. Eight patients were infected by blood or blood products from graft-related transfusions and one by the graft itself; the remaining two patients were infected after transplantation as a result of independent risk factors. All patients received a triple-drug immunosuppressive regimen including cyclosporine. After a mean follow-up of 52 months, chronic graft rejection was documented in four cases.
The cumulative incidences of HIV-related complications and HIV-related deaths were 82% and 27%, respectively, and three patients died rapidly from HIV-related complications. Encouraging, though, was the seven-year survival rate reported: 36% among the 11 perioperative-infected patients and 70% among the patients infected after transplantation.
A third report, published in 1990, involved 15 HIV-positive liver recipients (Tzakis, 1990). After a mean follow-up of 12.75 years, 2/15 (13%) patients were still alive, one of whom was infected prior to transplantation and one of whom was infected perioperatively. Interestingly, both patients who are still alive began HAART within the years following transplantation. Of the 13 patients who died during the follow-up period, only one reported using HAART.
|The Pittsburgh Experience
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Anecdotally, Dr. Fung has reported his experience with five liver-transplant patients and two kidney-transplant patients, all of whom were receiving HAART prior to transplantation. Coincidentally, the five liver recipients were receiving a protease inhibitor-based regimen, and the two kidney recipients were receiving a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen.
Tacrolimus was the calcineurin inhibitor selected by Dr. Fung to treat these patients postoperatively. "This drug needs to be used carefully in patients receiving either a protease inhibitor or an NNRTI," cautioned Dr. Roland. "Protease inhibitors increase tacrolimus levels dramatically. In patients receiving a protease inhibitor, tacrolimus is being dosed by Dr. Fung at one to two milligrams a week. For patients receiving an NNRTI, there is still a need for caution, and the dose used in Pittsburgh was 0.1 mg/kg/day."
To date, Dr. Fung has reported one death and one case of chronic rejection. "The circumstances behind this unfortunate rejection case should give us pause," Dr. Roland said. "During his recovery, the patient's doctor initiated an antiretroviral-drug holiday. The patient had stopped taking his protease inhibitor, and this was not reported back to the transplant team. Because there was no longer a P450 interaction during this time, the tacrolimus dose was too low. Communication among all clinicians and the patients and careful watching for drug interactions is a must."
Four of the liver recipients are still alive, all of whom underwent transplantation because of HCV-associated liver disease. The fifth patient underwent transplantation because of NRTI-induced hepatic failure and died shortly after the procedure. The longest follow-up time has been 2.5 years for one of the liver recipients. Unfortunately, three of the four liver recipients have experienced a recurrence of HCV. Treatment with interferon-alpha and ribavirin (Rebetron) was initiated in all three patients, and one patient has since remained HCV-RNA negative.
With respect to HIV progression, all transplant recipients have maintained an undetectable viral load and now have CD4+ counts above 200 cells/mm3. "We're all encouraged by the lack of HIV disease progression in these patients," Dr. Roland said. "There haven't been any viral rebounds and the CD4+ cell counts are holding strong. The clincher is the two-and-a-half-year survival in one of his patients. We're not sure if we'll see this in the UCSF study, but it's definitely what we're after."
|The UCSF Study
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CD4+ cell count and viral load criteria vary for potential kidney and liver recipients. Kidney transplant recipients must have been on a stable antiretroviral regimen for three months prior to study entry and have an undetectable viral load (<50 copies/mL) and a CD4+ count of at least 200 cells/mm3. Liver recipients must have a CD4+ count of at least 100 cells/mm3. Patients are also required to have an undetectable viral load while on a stable regimen.
Patients will be followed for five years. Most follow-up visits will take place in an outpatient setting, with the exception of five inpatient visits to the General Clinical Research Center (GCRC) for the necessary pharmacokinetic studies. Of course, patients who experience organ rejection or require medication-dosing adjustments will be hospitalized in the GCRC for additional PK monitoring.
The immunosuppressives used in the study are similar to those used in standard transplantation cases. Prednisone, mycophenylate, and a calcineurin inhibitor (either tacrolimus or cyclosporine) can be used. Of course, the calcineurin inhibitor dose will depend on P450 interactions and patients. Moreover, providers and patients will be alerted to the fact that mycophenylate and stavudine or zidovudine are possibly antagonistic and that concomitant use should be avoided when possible, given issues of resistance and tolerability. Dr. Roland noted that the use of calcineurin inhibitors in HIV-positive patients is interesting. Calcineurin inhibition, particularly cyclosporine, halts CD4+ cell proliferation. While on one level this may seem counterproductive, slowing CD4+ cell proliferation actually decreases the number of available HIV targets. "There have been retrospective reviews indicating that certain immunosuppressive regimens decrease HIV-disease progression," Dr. Roland explained. "We're not sure why this is, but it may be that these drugs decrease immune system over activation, one of the hypothesized mechanisms associated with HIV infection. Cyclosporine is also believed to have direct anti-HIV activity through interactions with cyclophilin."
Four substudies have been built into the Midgen HIV Transplant Initiative. The first is the pharmacokinetics assessment. Patients will be admitted to the hospital and plasma samples will be evaluated over 24 hours for immunosuppressant, protease inhibitor, and NNRTI concentrations (see Figure 1 for preliminary drug-drug interactions data reported at the Eighth Conference on Retroviruses and Opportunistic Infections in February). Urine toxicology screening will also be conducted to look for illegal and other prescription drugs, not for study exclusion, but for other drug-drug interactions.
The second is a study of human papillomavirus (HPV) or, more specifically, the development of cervical or anorectal dysplasia and neoplasia in the transplant recipients. Dr. Roland explained that, "people with HIV and patients who receive transplants are at an increased risk for the development of cervical and anorectal dysplasia. We want to make sure that transplantation in HIV-positive patients doesn't accelerate this process even more. We'll be following clinical and pathologic signs of dysplasia and carcinoma with serial colposcopic exams, Pap smears, and biopsy if indicated."
The third substudy involves human herpes virus-8 (HHV-8), the virus believed to be the cause of KS, Castleman's disease, and body cavity-based lymphomas. Patients will be tested for HHV-8 and quantitative HHV-8 viral load in blood plasma and cells; immunologic studies related to HHV-8 will also be conducted.
The fourth substudy will look at the immunologic consequences of transplant and immunosuppression in the patients enrolled. The immunologic parameters to be evaluated include, but are not limited to: peripheral blood phenotyping to assess the composition of circulating subpopulations of lymphocytes (e.g., naive vs. memory cells); lymphocyte proliferative response (LPR) assays to asses changes in response to alloantigen, phytohemagglutin, and recall antigens; natural killer cell function; CD8+ cell-suppressing activity; chimerism studies; and chest CT scans to assess thymic index.
The current level of funding from the State of California will only enable UCSF to provide clinical and research evaluations for approximately 15 recipients of kidney or liver transplants, all of whom must be California residents. While funds are available to cover the costs of transplantation, Dr. Roland and her team are working closely with third-party reimbursement programs to encourage them to cover the clinical costs. "This will allow us to stretch our funding dollars and cover as many interested and eligible HIV-positive patients as possible, and learn as much as possible by maximizing the research opportunities."
To further the goals of this pilot study, Drs. Roland and Stock have been working with clinicians and investigators from around the country to put together a multisite study with a common protocol and a centralized data collection and analysis facility. The National Institutes of Health have kicked in approximately $300,000 to help pay for data collection and lab work, but the bulk of necessary funding will need to come from private insurers to cover the costs of transplantation surgery and postoperative care.
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The first patient, a 15-year-old male who was coinfected with HCV and HIV, received a liver-lobe donation from his mother. After transplantation, decompensated liver disease occurred, and a second transplant-involving a cadaveric liver and kidney-was performed. The remaining four patients all received kidney transplants, one from a living donor and the other three from cadavers. "They're all doing quite well," offered Dr. Roland in her closing remarks. "All of them, with the exception of the first patient, have been able to maintain undetectable viral loads and have CD4+ counts about 200 cells/mm3. We're now screening several patients and we're expecting to produce some interesting data in the months and years to come."
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