Prior to the introduction of HAART, the morbidity and mortality of HIV-infected patients was too high to justify using scarce resources in transplanting HIV-infected patients [98
]. There were concerns that immunosuppression may exacerbate HIV replication in an already immunocompromised patient resulting in rapid progression of disease and increased mortality [144
]. The ability to suppress HIV replication with HAART, as well as improved prophylaxis and treatment of opportunistic infections, encouraged the transplant community to reconsider this option in HIV-infected individuals.
Further impetus was provided by the serendipitous finding that many of the commonly used immunosuppressive agents were also effective against HIV. Cyclosporine inhibition of interleukin-2-dependent T-cell proliferation may suppress HIV replication [145
]. Furthermore, by binding to cyclophyllin A, cyclosporin prevents the formation of HIV gag protein/cyclophyllin A complex necessary for nuclear transport of HIV DNA [147
]. A prospective study showed more rapid immune reconstitution in HIV-infected patients treated with cyclosporine and HAART versus cyclosporine alone [149
]. Mycophenolate mofetil (MMF) inhibits inosine monophosphate dehydrogenase, a rate-limiting enzyme in the synthesis of guanosine nucleotides, markedly decreasing intracellular nucleotides in lymphocytes and monocytes as these cells lack a salvage pathway for generating purines, and thereby preventing replication of these cells [150
]. Hence, MMF can provide synergistic action with nucleotide analogues such as abacavir and didanosine, which are often integral components of HAART therapy [152
]. Of potential concern is the in vitro antagonism with stavudine and zidovudine that may inhibit the action of MMF. However, this has not been demonstrated in vivo [144
]. Sirolimus inhibits the mammalian target of the rapamycin (mTOR) pathway by directly binding the mTOR Complex1 (mTORC1) that down-regulates the CCR5 receptor, which is the T-cell co-receptor for the HIV virion [154
Transplants performed in HIV-infected patients on HAART show one-year graft and patient survival rates comparable to HIV-uninfected patients, although acute rejections are seen more frequently in the former, at a rate double that seen in those that are uninfected [144
]. It has been postulated that this may be the result of immune dysregulation, but could also represent incomplete immunosuppression due to changes in overall drug exposure. Higher acute rejection rates have been observed in patients of African descent [155
The “Transplant Study for People with HIV” (www.HIVtransplant.com
) has proposed selection criteria that continue to evolve as more experience accumulates in this group of transplant patients [158
]. The inclusion criteria for selecting a suitable kidney transplant recipient with HIV-infection include, inter alia
- Meeting the standard criteria for kidney transplantation.
- In children, the percentage of CD4+T-cell is better than an absolute CD4+T-cell count in defining an intact immune system, hence modification of criteria to include a T-cell percentage. For children 1–2 years of age, the T-cell percentage must be >30%, and in children 2–10 years of age it must be >20%.
Undetectable viral load (<50 copies/mL) for more than 6 months.
- No change in the HAART regimen for at least 3 months prior to kidney transplantation.
- There must be compliance to treatment for at least 6 months and caregivers and/or recipients must demonstrate willingness and an ability to comply with the immunosuppression protocol, ARV therapy and prophylaxis for opportunistic infections.
- In the case of pulmonary coccidiodomycosis, the recipient must be disease-free for at least 5 years prior to kidney transplantation and in the case of neoplasms, for at least 2 years.
- Female candidates of child-bearing potential must have a negative serum human chorionic gonadotropin pregnancy test 14 days prior to transplantation. All candidates must practice barrier contraception.
- The ability to provide informed consent and, for children between 7 and 12 years, signed assent. In the case of minors between the ages of 13 and 18 years, the minor and parent(s) must both provide informed consent. These ages may vary according to the laws and Institutional Review Boards of various regions.
Exclusion criteria include, inter alia
, the following:
- Advanced-cardio-pulmonary disease.
- Active uncontrolled malignancy with reduced life span;
- Significant infection which may flare or reactivate with immunosuppression, such as tuberculosis, aspergillosis and other fungal infections, severe bacterial infections and active human papilloma virus infection.
- Documented progressive multifocal leukoencephalopathy.
- Epstein-Barr virus and human herpes virus 8 associated lymphoproliferative disease.
- Documented poor compliance.
- Failure to obtain informed consent or where required, assent.
Pharmacokinetic interactions between immunosuppresants and HAART agents can be profound with the most notable drug interactions occurring between ARV agents and immunosuppressive agents that induce or inhibit the P-glycoprotein 1 flux transporters and the cytochrome P450 3A (CYP3A4)-metabolizing enzymes found in the gut and liver [98
]. Interactions can lead to unexpected increases or decreases in drug plasma levels and result in organ rejection, toxic adverse reactions of drugs and possible exacerbation of HIV replication. Patients on PIs and cyclosporine require only about 20% of the immunosuppressant dose of the latter drug normally administered to renal transplant recipients without HIV [98
]. Patients on a ritonavir-boosted PI regimen require even lower doses of calcineurin inhibitors than patients on other HAART regimens [159
]. In patients on tacrolimus or sirolimus using PIs as part of HAART, not only is the dose of these immunosuppresive drugs markedly decreased, but the interval of dosing needs to be increased more than five-fold [98
]. Azole antifungal and macrolide antibiotics also inhibit the CYP3A4 system, increasing immunosuppressant levels of calcineurin inhibitors and sirolimus [160
]. Patients taking steroids usually need proton-pump inhibitors for gastric ulcer prophylaxis. Since proton pump inhibitors can reduce intestinal absorption of Atazanavir, this PI must always be used in conjunction with a boosting dose of ritonavir. Zidovudine as a component of HAART used in combination with MMF could lead to additive myelosuppressive effects [161
Post-transplant prophylaxis used in HIV-infected kidney transplant recipients is the same as that in HIV-uninfected recipients [98
]. These regimens include prophylaxis for CMV and fungal infections (including Pneumocystis jiroveci
) in the early postoperative period. For those patients with acute rejection treated with lymphocyte-depleting agents, prophylaxis regimen should be resumed for 3–6 months after discontinuation of the anti-rejection treatment.
Although HIV-infected adults are at increased risk for cancers such as Kaposi's sarcoma and non-Hodgkin's lymphoma, the rates of these cancers have declined with the introduction of HAART [162
]. In adults, however, hepatocellular carcinoma rates have increased and this is probably related to increased longevity of patients with HIV co-infected with hepatitis B or C [164
]. There are no similar reports in children.
In summary, kidney transplantation in HIV-infected patients treated with HAART has shown excellent graft and patient survival rates at 3–5 years [156
]. Most issues revolve around interactions between ARV agents and the immunosuppressive agents used to prevent rejection. Opportunistic infections in these patients do not seem to have considerably increased although these patients have higher rates of acute rejection. Hepatitis B and C co-infection in adults remain a major concern, both in terms of treatment options and long-term effects on progression of liver disease [98
Based on the current evidence, exclusion of children with HIV-infection from receiving a kidney transplant can no longer be justified.