The introduction of highly active antiretroviral therapy (HAART) dramatically changed the HIV epidemic in the United States and is responsible for an 80% decline in HIV death rates (1, 2). Not surprisingly, chronic diseases have now replaced opportunistic infections as the leading cause of death among HIV-positive patients (3); in fact, end-stage renal disease (ESRD) now accounts for 12.2% of all HIV-related deaths (4). Approximately 1.5% of ESRD patients on dialysis are HIV positive (5), and HIV-associated nephropathy is now the third leading cause of renal failure among African Americans (6). Multiple studies have linked ESRD to increased mortality among HIV-positive individuals, documenting mortality rates as high as 48% in the setting of low glomerular filtration rate and proteinuria (7–10). Although HIV infection was initially considered a contraindication to kidney transplantation (KT), the role for KT among HIV-positive ESRD patients has recently been revisited in the context of improved outcomes (11, 12).
Stock et al. conducted the largest, National Institutes of Health–funded, prospective multicenter investigation of KT in HIV-positive ESRD patients on HAART (12). Potential candidates were required to have an undetectable HIV viral load, CD4 count greater than 200, and a stable HAART regimen; both induction and maintenance immunosuppression regimen choices were left to center discretion. Patient and graft survival at 1 year were 94.6% and 90.4%, which were lower than those of their HIV-negative counterparts but comparable with older HIV-negative recipients. Furthermore, few HIV-positive recipients had disease progression. Perhaps somewhat paradoxically, acute rejection (AR) incidence was 31% at 1 year and 41% at 3 years, about three to four times that reported in HIV-negative recipients. Not surprisingly, the risk of graft loss was 2.8-fold higher among those HIV-positive patients treated for AR (hazard ratio, 2.8; 95% confidence interval [CI], 1.2–6.6; P=0.02).
Although Stock et al.’s study, and those of others (11, 13, 14), have demonstrated that KT is feasible in HIV-positive patients, the high rates of AR seen in this population are worrisome and raise questions about appropriate immunosuppression management (12, 15–19). Among HIV-negative individuals, many studies have documented the relationship between immunosuppression regimen choice and the risk of AR; unfortunately, these relationships remain poorly understood in the HIV-positive population (20–22). In this unique population, the development of an optimal immunosuppression regimen must be balanced against the increased risks of opportunistic infections and worsening of underlying HIV infection, so the relevance of evidence derived from HIV-negative individuals is unclear at best.
Better understanding of the relationship between immunosuppression regimen, rejection, and infectious risk among HIV-positive KT recipients is of paramount importance to ensure continued safe delivery and even expansion of KT for this vulnerable patient population (23). We therefore sought to examine the associations between immunosuppression regimen, AR rates at 1 year and patient and graft survival among a large cohort of HIV-positive KT recipients.
Compared with the general pool of HIV-negative recipients, the 516 HIV-positive recipients were younger. Fifty-eight percent of whom were less than 50 years old. In addition, 64.5% of HIV-positive recipients were African American compared with only 29.2% of HIV-negative recipients (P<0.001). HIV-positive recipients were also less likely to have received a living-donor kidney (28.1% vs. 38.2%, respectively; P<0.001). Cold ischemia time (CIT) was 2.3 hr longer among the HIV-positive cohort (P<0.001) (Table 1).
HIV-positive recipients more often received no induction immunosuppression (35.1% vs. 21.4%; P<0.001). Only 25.8% of HIV-positive recipients received antithymocyte globulin (ATG) induction compared with 43.5% of HIV-negative recipients (P<0.001). The most common induction agents used in HIV-positive patients were interleukin (IL)-2 inhibitors. More than 80% of HIV-positive and HIV-negative recipients were maintained on calcineurin inhibitor (CNI)–based immunosuppression regimen (Table 2).
Fifteen percent of HIV-positive patients experienced an episode of AR within the first posttransplantation year compared with only 8% of HIV-negative patients (P<0.001). After adjusting for donor, recipient, and center factors, HIV-positive patients had a 1.77-fold higher risk of AR at 1 year compared with their HIV-negative counterparts (adjusted relative risk [aRR], 1.77; 95% CI, 1.45–2.2; P<0.001). However, among HIV-positive and HIV-negative patients receiving ATG induction therapy, the risk of AR was 1.16 and was not statistically different (aRR, 1.16; 95% CI, 0.41–3.35; P=0.77). Furthermore, HIV-positive patients that received ATG induction had a 2.6-fold or 61% lower risk of AR at 1 year (aRR, 0.39; 95% CI, 0.18–0.87; P=0.02) compared with no induction therapy. Compared with CNI-based maintenance therapy, HIV-positive recipients maintained on sirolimus-based therapy had a 2.2-fold higher risk of AR at 1 year (aRR, 2.15; 95% CI, 1.20–3.87; P=0.01; Table 3).
Overall, HIV-positive KT recipients had a higher risk of graft loss compared with HIV-negative kidney recipients (adjusted hazard ratio, 1.51; 95% CI, 1.18–1.94; P=0.001). However, in matched control analyses comparing HIV-positive and HIV-negative patients that received ATG induction therapy, there was no difference in death-censored graft survival (DCGS) at 1 year (91.7% [84%–95%] vs. 94.2% [88%–97%], respectively; P>0.05, log-rank; Fig. 1). Furthermore, there was no difference in patient survival at 1 year (98% [92%–99%] vs. 96.6% [91%–98%], respectively, P>0.05, log-rank; Fig. 2).
In this national study of 516 HIV-positive adults undergoing kidney-only transplantation, we found that the incidence of AR at 1 year was 1.77-fold higher among HIV-positive compared with HIV-negative KT recipients. However, in the setting of ATG induction therapy, we found no difference in the risk of AR at 1 year among HIV-positive and HIV-negative recipients. Furthermore, among HIV-positive recipients, ATG induction therapy was associated with a 2.6-fold lower risk of AR at 1 year; conversely, sirolimus-based maintenance immunosuppression regimen was associated with a 2.2-fold higher risk of AR at 1 year compared with CNI-based regimen. Moreover, ATG induction therapy was associated with similar patient and graft survival rates among HIV-positive and HIV-negative KT recipients.
Previous studies have documented high rates of AR among HIV-positive KT recipients, ranging from 13% to 52% at 1 year, generating legitimate concern among the transplant community regarding the immunosuppression management of this complex patient population (14–17, 19, 24, 25). Explanations for higher rates of AR among the HIV-positive population remain unclear, but it is likely that immunologic, pharmacologic, and/or racial factors all play a role. Concerns remain about the potential additive effects of immunosuppression agents and HIV on the risk of opportunistic infections and malignancies. As a result, the use of lymphocyte-depleting agents, such as ATG, have been avoided because these agents are known to severely deplete CD4 counts for months and may place HIV-positive individuals at higher risk for the development of opportunistic infections (24, 25).
Despite these concerns, it is difficult to ignore the robust alloimmune response among HIV-positive KT recipients as reflected in their higher than expected AR rates (26). Clearly, as with all transplant recipients, independent of HIV status, the risk of infection must be balanced by the risk of allograft loss secondary to AR. Although our data were limited by the lack of information about CD4 counts, malignancies, and infections in the context of induction immunosuppression choice, the 2.6-fold reduction in AR at 1 year among those HIV-positive patients receiving ATG induction therapy was significant and should be given serious consideration. Interestingly, less than one-third of HIV-positive patients receive ATG induction therapy. This may be related to the work of Stock et al., in which they found twice as many infections among HIV-positive KT recipients who received ATG (0.9 vs. 0.4; P=0.002) (12). Their data demonstrated, however, that this higher than expected rate of infection was not associated with worse patient survival, suggesting that, although an increased number of infections were observed, the infections were not life-threatening. Our results confirmed this observation, as there was no difference in patient survival among HIV-positive and HIV-negative patients receiving ATG induction therapy.
The optimal maintenance immunosuppression therapy among HIV-positive KT recipients remains to be elucidated. Drug interactions resulting in altered exposure to maintenance immunosuppressants and lower therapeutic levels may be responsible for the higher rates of AR seen in this patient population (19). This may be particularly true for sirolimus-based regimens, which require longer periods of time to achieve steady-state drug levels. In fact, our data demonstrated a 2.2-fold higher risk of AR at 1 year with the use of sirolimus-based maintenance immunosuppression regimen. As newer antiretrovirals come to market, such as integrase inhibitors that have no interactions with maintenance immunosuppressants, it is likely that HIV-positive KT recipients will be able to achieve consistently therapeutic immunosuppressant drug levels and therefore lower their risk of AR (27).
Inferences based on our findings must take into account a number of important limitations in study design and data availability. Scientific Registry of Transplant Recipients (SRTR) data lack granularity with regard to infections and malignancies after transplantation; therefore, it is difficult to determine the impact of increased immunosuppression on these factors among HIV-positive KT recipients. However, the work of Stock et al. demonstrates that the higher than expected rate of infection was not associated with worse patient survival. This suggests that, although there may be an increased number of infections among HIV-positive recipients receiving ATG induction, the infections were not life-threatening. Further, our results confirmed this observation, as there was no difference in patient survival among HIV-positive and HIV-negative patients receiving ATG induction therapy. Furthermore, immunosuppressant levels and antiviral regimen are not captured by SRTR data, and as such, it is impossible to determine whether drug interactions between HAART therapy and maintenance immunosuppressants lead to subtherapeutic drug levels and higher rates of rejection. It has been established, however, that more than 80% of patients are maintained on protease inhibitor–based HAART and CNI-based maintenance immunosuppression. Therefore, the theoretical risk of higher rejection rates secondary to these drug interactions should be evenly distributed across all patients independent of induction agent, and as such, immunosuppressant levels and HAART are at worst confounders, not effect modifiers. Moreover, individual provider and center preference strongly influences choice of both induction and maintenance immunosuppression, and our analyses cannot account for this potential treatment selection bias. Finally, the sample size available for the subgroup analyses was relatively small and, as such, may directly impact the accuracy of our estimates. However, these data represent the HIV-positive KT population in the United States in its totality and, as such, contribute new and important information about optimal induction therapy in this unique patient population.
Individuals infected with HIV are living longer and consequently beginning to suffer from more chronic diseases such as ESRD, bringing KT to the forefront among this patient population (3). Developing strategies to reduce the risk of AR remains of paramount importance. Although much is left to learn about the management of HIV-positive KT recipients, ATG appears to be the induction therapy of choice to reduce the risk of AR among this highly selected population. Furthermore, ATG induction therapy appears to afford HIV-positive patients similar graft and patient survival as HIV-negative patients. Additional studies are necessary to better understand the association between utilization of this agent and the development of malignancies and opportunistic infections among HIV-positive KT recipients.
MATERIALS AND METHODS
All adult kidney-only transplants, with known HIV status, between November 1, 2003 and December 31, 2011 were identified (n=93,543) using the SRTR. The SRTR data system includes data, submitted by the members of the Organ Procurement and Transplantation Network, on all donors, waitlisted candidates, and transplant recipients in the United States. The Health Resources and Services Administration of the U.S. Department of Health and Human Services provides the oversight to the activities of the Organ Procurement and Transplantation Network and SRTR contractors. Patients with multiple induction drugs listed (n=4440 [HIV positive, n=51]) and those missing information on donation after cardiac death (DCD; n=2), panel-reactive antibody (PRA; n=1794 [HIV positive, n=15]), or human leukocyte antigen (HLA) mismatch data (n=362 [HIV positive, n=2]) were excluded from analysis (two patients were missing both PRA and HLA mismatch data).
Induction immunosuppression was divided into four categories: no induction, ATG, IL-2 receptor antagonists, and alemtuzumab. Maintenance immunosuppression was defined as the therapy regimen at the time of initial discharge from the hospital and was categorized into three groups: CNI-based, sirolimus-based, and other.
The primary outcome measure was AR within 1 year after transplantation. Patients with less than 1 year of follow-up or with no follow-up information were excluded from analyses with AR as the outcome. Secondary outcomes included patient survival and DCGS. Patient survival was defined as the time from transplantation to death or last follow-up. DCGS was defined as the time from transplantation to the earliest of graft loss, return to dialysis, or last follow-up with a functioning graft, censored for death. Death indicators were supplemented by linkage to the Social Security Death Master File; death and graft loss were supplemented by linkage to data from the Centers for Medicare and Medicaid Services. Both patient survival and DCGS were censored for administrative end of study.
Donor age, type (living versus deceased, including DCD and expanded-criteria donor), and CIT were collected, as were recipient age, race, PRA, HLA mismatch, and history of retransplantation. In addition, we also adjusted for center experience, fit empirically as a dichotomous measure of more than six KTs in HIV-positive recipients during the study period.
Donor, recipient, and center characteristics among HIV-positive and HIV-negative kidney-only transplant recipients were compared. Continuous variables were analyzed using t tests or Wilcoxon rank-sum tests (based on distribution) and categorical variables were examined using chi-square or Fisher’s exact tests of independence (based on sample size). AR at 1 year was compared between HIV-positive and HIV-negative using modified multivariate Poisson regression models adjusted for donor, recipient, and center-level factors as described above. Patient survival and DCGS were compared between HIV-positive and HIV-negative recipients using Kaplan–Meier survival estimates and log-rank tests. The risks of graft loss and patient death were compared between HIV-positive and HIV-negative using multivariate Cox proportional hazards models adjusted for donor, recipient, and center-level factors as described above. All of the tests were two-sided with statistical significance set at α=0.05. Analyses were performed using Stata 12.1/SE (College Station, TX).
Sensitivity Analysis: Matched Controls
Multivariate models comparing a small subgroup (such as HIV-positive recipients) with large groups (such as HIV-negative recipients) have inherent instability. To confirm that our inferences were not sensitive to this limitation of multivariate regression models, we also performed a matched controls analysis. Specifically, HIV-positive recipients who received induction immunosuppression with ATG were matched with one similarly treated HIV-negative recipient using iterative expanding radius matching as described previously (28) based on donor type (living or deceased), recipient age and race, PRA, number of HLA mismatches, and previous transplant. Patient survival and DCGS between matched controls were compared.
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