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Association Between Duration of Human Immunodeficiency Virus (HIV)–1 Viral Suppression Prior to Renal Transplantation and Acute Cellular Rejection

2016; Elsevier BV; Volume: 17; Issue: 2 Linguagem: Inglês

10.1111/ajt.13985

1600-6143

Jennifer Husson, Kristen A. Stafford, Jonathan S. Bromberg, Abdolreza Haririan, Tracy Sparkes, Charles E. Davis, Robert Redfield, Antonio Amoroso,

HIV/AIDS Research and Interventions

Renal transplant has become an important option for human immunodeficiency virus (HIV)–infected patients with end-stage renal disease; however, these patients experience a high rate of acute cellular rejection (ACR). Guidelines do not currently exist for the optimal duration of viral suppression prior to transplantation. In a retrospective cohort analysis of 47 HIV-infected renal transplant recipients, we compared the rate of ACR between patients based on the length of time of viral suppression prior to transplantation. Of the patients who achieved viral suppression for >6 months but less than 2 years prior to transplantation (n = 15), 60% experienced ACR compared to 41% of patients suppressed at least 2 years or more (n = 32) prior to transplant (p = 0.21). Patients suppressed 6 months but less than 2 years prior to transplantation (n = 15), 60% experienced ACR compared to 41% of patients suppressed at least 2 years or more (n = 32) prior to transplant (p = 0.21). Patients suppressed 200 cells/mL. Patients received induction therapy according to our protocol with either basiliximab or antithymocyte globulin (ATG). All patients were placed on maintenance immunosuppression posttransplantation with mycophenolate, prednisone and a calcineurin inhibitor with tacrolimus trough goals of 8–9 ng/mL. In an effort to make the comparison group more homogenous with respect to factors that could influence ACR, we restricted the study sample to patients on the same maintenance therapy posttransplant. Antiretroviral regimens were determined by the patients' HIV providers, in an attempt to minimize drug–drug interactions where permissible based upon each patient's genotype and prior drug exposure history. The primary outcome variable for this study was ACR as ascertained by renal biopsy. The renal biopsies were evaluated and graded using the Banff system by a pathologist. The predictor variable was duration of HIV viral suppression prior to transplant. The date of suppression was obtained through patient records and further defined as the time patients attained a viral load of 200. Baseline variables investigated as potential confounders included sex, age, race, time since HIV diagnosis at time of transplant, hepatitis B infection, HCV infection, cytomegalovirus (CMV) mismatch, HLA mismatch, panel-reactive antibody (PRA) I, PRA II, donor type and induction therapy drug class. Data were first investigated using univariate analysis to describe the frequency and distribution of the outcome, primary exposure and covariates. The effect of duration of viral suppression on ACR was investigated using quantile regression analysis to initially select cut points for further investigation. The crude association between duration of viral suppression and ACR was initially investigated in bivariate analysis using an unadjusted Cox proportional hazard model. Time-to-event analysis was performed using the Kaplan–Meier method. Differences in time to event were evaluated using the Wilcoxon rank-sum p-value. Patients who did not experience ACR were censored at the end of their follow-up time or at the end of the study period. Covariates were maintained in the adjusted model if they changed the beta estimate for the crude hazard ratio for the association between duration of viral suppression and ACR by 20% or if the partial likelihood ratio test for the covariate was significant at an alpha level of 0.1. The proportional hazards assumption was assessed by plotting the scaled and smoothed scaled Schoenfeld residuals and assessing covariate specific score tests. All statistical analyses were carried out using SAS 9.4 (SAS Institute Inc., Cary, NC). A total of 55 HIV-infected patients received a kidney transplant during the study period. Five patients who did not have a documented duration of viral suppression, two patients who were converted to rapamycin as maintenance suppressive therapy and one patient who underwent liver transplantation at the time of renal transplantation were excluded. Forty-seven patients were included in the study sample; of those, 68% of the study population was male and 96% was African American. Two years was selected as the cut point for comparison based on the exploratory, quantile regression analysis (data not shown). Of the 47 patients, 15 (32%) had been suppressed less than 2 years at the time of transplant (Table 1). Patients who had been suppressed 2 years or longer were not significantly different compared to those who had been suppressed less than 2 years in the distribution of most baseline covariates. Patients who had been suppressed less than 2 years had a lower median CD4 cell count at time of transplant (p = 0.02) compared to those suppressed 2 years or longer.Table 1:Baseline characteristics of HIV-infected kidney transplant recipients by duration of viral suppression at time of transplant (n = 47)CharacteristicTotal n = 47Duration of viral suppression at transplantp-value<2 years n = 15≥2 years n = 32Age, mean (SD), years50 (10)49 (10)52 (10)0.701student's t-testSex, n (%)0.422Male32 (68)9 (60)23 (72)–Female15 (32)6 (40)9 (28)–Race, n (%)0.543Fisher's exact test of proportions.African American45 (96)14 (93)31 (97)–White1 (2)0 (0)1 (3)–Other1 (2)1 (7)0 (0)–Hepatitis B, n (%)6 (12)1 (7)5 (16)0.653Fisher's exact test of proportions.Hepatitis C, n (%)17 (36)5 (33)12 (38)1.002Chi-square test of proportions.Time since HIV diagnosis at time of transplant, median (IQR), years12 (7–17)12 (9–16)13 (7–17)0.644Wilcoxon rank-sum two-sample test.CD4 cells/mm3 at time of transplant, median (IQR)436 (322–638)363 (267–450)520 (348–695)0.025Total number of patients across antiretroviral therapy (ART) type will exceed total number of patients per group based on full drug regimen; five patients missing regimen data.CD4 percentage at time of transplant, median (IQR)31 (24–36)29 (24–34)31 (24–37)0.504Wilcoxon rank-sum two-sample test.cART regimen, n (%)5Total number of patients across antiretroviral therapy (ART) type will exceed total number of patients per group based on full drug regimen; five patients missing regimen data.0.753Fisher's exact test of proportions.Other12 (26)4 (27)8 (25)–PI21 (45)7 (47)14 (44)–NNRTI10 (21)2 (13)8 (25)–PI and NNRTI4 (8)2 (13)2 (6)–Comorbidities, n (%)Diabetes mellitus12 (26)6 (40)6 (19)0.163Fisher's exact test of proportions.Hypertension46 (98)14 (93)32 (100)0.323Fisher's exact test of proportions.Stroke2 (4)0 (0)2 (6)1.003Fisher's exact test of proportions.Malignancy other than lymphoma4 (9)1 (7)3 (9)1.003Fisher's exact test of proportions.CMV mismatch, n (%)7 (15)4 (27)3 (9)0.193Fisher's exact test of proportions.HLA mismatch, n (%)6Fourteen patients missing HLA-I or II mismatch information (six in ≥2 year suppression group and two in <2 year group).0.743Fisher's exact test of proportions.0–415 (32)4 (27)11 (34)–5–632 (68)11 (73)21 (66)–PRA I peak, median (IQR)7Seven patients suppressed 2 years or longer and three patients suppressed less than 2 years missing PRA I data.0 (0–13)2 (0–22)0 (0–8)0.684Wilcoxon rank-sum two-sample test.PRA II peak, median (IQR)8Seven patients suppressed 2 years or longer and three patients suppressed less than 2 years missing PRA II data.0 (0–15)0 (0–22)0 (0–10)0.714Wilcoxon rank-sum two-sample test.Donor type, n (%)9Five patients missing data on donor type.0.243Fisher's exact test of proportions.Living related0 (0)0 (0)0 (0)–Living unrelated3 (6)2 (13)1 (3)–Deceased44 (94)13 (87)31 (97)–Induction therapy0.422Basiliximab29 (62)8 (53)21 (66)–Lymphocyte depleting18 (38)7 (47)11 (34)–HIV, human immunodeficiency virus; SD, standard deviation; IQR, interquartile range; cART, combined antiretroviral therapy; PI, protease inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; CMV, cytomegalovirus; PRA, panel-reactive antibody.1 student's t-test2 Chi-square test of proportions.3 Fisher's exact test of proportions.4 Wilcoxon rank-sum two-sample test.5 Total number of patients across antiretroviral therapy (ART) type will exceed total number of patients per group based on full drug regimen; five patients missing regimen data.6 Fourteen patients missing HLA-I or II mismatch information (six in ≥2 year suppression group and two in <2 year group).7 Seven patients suppressed 2 years or longer and three patients suppressed less than 2 years missing PRA I data.8 Seven patients suppressed 2 years or longer and three patients suppressed less than 2 years missing PRA II data.9 Five patients missing data on donor type. Open table in a new tab HIV, human immunodeficiency virus; SD, standard deviation; IQR, interquartile range; cART, combined antiretroviral therapy; PI, protease inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; CMV, cytomegalovirus; PRA, panel-reactive antibody. The median PRA I peak was significantly higher in patients who had been suppressed less than 2 years compared to those who had been suppressed 2 years or longer (4 vs. 0, p = 0.02). Patients who had been suppressed less than 2 years had higher degrees of HLA mismatch compared to patients suppressed 2 years or longer (56% with a mismatch of 5 or 6 compared to 44%, respectively; p = 0.06). Of the seven patients who were cytomegalovirus (CMV) mismatches, four (27%) had been suppressed less than 2 years compared to three (9%) who had been suppressed 2 years or longer (p = 0.19). The prevalence of opportunistic infections prior to transplant did not differ between the two groups (p = 0.95) (data not shown). The use of lymphocyte-depleting induction immunosuppression was more common among patients suppressed less than 2 years compared to patients suppressed 2 years or longer, but the proportions were not statistically different (47% vs. 34%, p = 0.42). A total of 22 patients (47%) experienced biopsy-confirmed ACR within 5 years of transplant. Sixty percent of patients who had been suppressed for less than 2 years experienced ACR compared to 41% of patients who had been suppressed for 2 years or longer (Figure 1). In the unadjusted analysis, patients suppressed less than 2 years had 2.23 times the rate of ACR compared to those suppressed 2 years or longer (95% confidence interval [CI]: 0.95–5.27, p = 0.07) (Table 2). The Kaplan–Meier curve for time to ACR by duration of viral suppression demonstrated that at all time points, a larger proportion of patients who had been suppressed less than 2 years had experienced ACR compared to patients who had been suppressed 2 years or longer (Figure 2). There was no difference in mean tacrolimus levels at set time points (7 days, 1 month, 3 months, 6 months, 1 year, 2 years, etc.) between the two groups (data not shown). After adjusting for the presence of chronic HCV infection and a total HLA mismatch of 5 or 6, the rate of ACR in those suppressed for less than 2 years was 2.48 (95% CI: 1.01–6.13) times the rate of patients suppressed for 2 years or longer (Table 3). The effect of ART regimen type on the rate of ACR also did not significantly differ between the two groups.Table 2:Unadjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for acute cellular rejection of kidney transplant among HIV-infected recipients by duration of viral suppression at time of transplant (n = 47)CharacteristicHR95% CIp-valueDuration of viral suppression prior to transplant≥2 years1.0––<2 years2.230.95–5.270.07Age, years32–491.0––50–730.530.22–1.310.17SexMale1.0––Female0.880.37–2.100.78Hepatitis BNo1.0––Yes1.210.36–4.080.76Hepatitis CNo1.0––Yes2.190.95–5.090.07CD4 cells/mm3 at time of transplant<5001.0––≥5001.050.44–2.490.91cART regimenOther1.0––PI1.490.48–4.690.49NNRTI1.650.44–6.150.46PI and NNRTI2.430.44–13.370.31Diabetes mellitusNo1.0––Yes2.000.81–4.920.13CMV mismatchNo1.0––Yes0.950.28–2.200.93HLA mismatch0–41.0––5–62.380.81–7.050.12PRA I peak0–41.0––≥52.240.96–5.220.06PRA II peak0–41.0––≥51.310.53–3.210.56Donor typeLiving unrelated1.0––Deceased1.510.20–11.240.69Induction therapyBasiliximab1.0––Lymphocyte depleting1.230.53–2.910.62HIV, human immunodeficiency virus; cART, combined antiretroviral therapy; PI, protease inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; CMV, cytomegalovirus; PRA, panel-reactive antibody. Open table in a new tab Figure 2:Kaplan–Meier curve of time to acute cellular rejection within 2 years of kidney transplant amongHIV-infected patients by duration of viral suppression at the time of transplant. p = 0.02. HIV, human immunodeficiency virus.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 3:Unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for acute cellular rejection of kidney transplant by 2 years posttransplant among HIV-infected recipients by duration of viral suppression at time of transplant (n = 47)CharacteristicHR95% CIp-valueAdjusted HR1Adjusted for hepatitis C coinfection and HLA mismatch.95% CIp-valueDuration of viral suppression at time of transplant≥2 years1.0––1.0–– 400 copies/mL) in five patients, four of whom had viral loads >1000 copies/mL. Of the five viremic patients, four had been suppressed for at least 2 years, and three of those four experienced an episode of ACR. Similarly, there were only six episodes of CMV viremia in five patients posttransplant and 11 patients who experienced BK nephropathy. Given the infrequency of these events, we were unable to further assess their association with ACR. Several studies have now shown high rates of acute rejection in HIV-infected renal transplant recipients compared to HIV-uninfected recipients. Within our cohort, we noted an ACR rate of 47% at 5 years, which is consistent with reported rates in the literature (4Stock PG Barin B Murphy B et al.Outcomes of kidney transplantation in HIV-infected recipients.N Engl J Med. 2010; 363: 2004-2014Crossref PubMed Scopus (378) Google Scholar, 5Kumar MS Sierka DR Damask AM et al.Safety and success of kidney transplantation and concomittant immunosuppression in HIV-positive patients.Kidney Int. 2005; 67: 1622-1629Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 6Malat GE Ranganna KM Sikalas N Liu L Jindal RM Doyle A High frequency of rejections in HIV-positive recipients of kidney transplantation: A single center prospective trial.Transplantation. 2012; 94: 1020-1024Crossref PubMed Scopus (30) Google Scholar, 7Qui J Terasaki PI Kayo W Cai J Gjertson DW HIV-positive renal recipients can achieve survival rates similar to those of HIV-negative patients.Transplantation. 2006; 81: 1658-1661Crossref PubMed Scopus (77) Google Scholar, 8Roland ME Barin B Carlson L et al.HIV-infected liver and kidney transplant recipients: 1- and 3-year outcomes.Am J Transplant. 2008; 8: 355-365Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Despite antiretroviral suppression of viremia, viral persistence and continued immune activation can be found, particularly in patients with lower CD4 counts (13Hatano H Jain V Hunt PW et al.Cell-based measures of viral persistence are associated with immune activation and programmed cell death protein 1 (PD-1)-expressing CD4+ T cells.J Infect Dis. 2013; 208: 50-56Crossref PubMed Scopus (179) Google Scholar). This persistent immune activation could be a potential causative factor in the increased rate of rejection experienced by HIV-infected renal transplant recipients. The use of lymphocyte-depleting induction therapy has been shown to decrease the rate of rejection 2.6-fold, further supporting a role for ongoing immune activation in this population (14Locke JE James NT Mannon RB et al.Immunosuppression regimen and the risk of acute rejection in HIV-infected kidney transplant recipients.Transplantation. 2014; 97: 446-450Crossref PubMed Scopus (66) Google Scholar). Although those suppressed for less than 2 years were more likely to have received lymphocyte-depleting induction therapy, we found no significant differences in the hazard ratio for ACR based upon the induction therapy used between our two groups, consistent with our previous findings (9Manitpisitkul W Sparkes T Pickard M Choice of induction in HIV-infected kidney transplant recipients and its impact on transplant outcomes. World Transplant Congress. American Journal of Transplantation, San Francisco2014Google Scholar). This discrepancy could imply that the use of lymphocyte-depleting induction therapy alone is not enough to prevent ACR in this population and that targeting immune activation via alternative approaches may be required. Based on our clinical observations, we hypothesized that a longer duration of viral suppression prior to transplantation would have a favorable impact on the incidence and time to rejection. We chose a breakpoint of 2 years for our analysis, and we found a cumulative incidence of ACR of 60% compared to 41% in those suppressed less than 2 years compared to those suppressed 2 years or longer. This difference was more pronounced at 2 years than at 1 year, with little further improvement looking at a breakpoint of 3 years (data not shown). Because five patients were excluded from the study due to missing data on duration of viral suppression, we performed sensitivity analyses and found no difference in the beta estimate for the hazard ratio. Given the unique population, the size of the study sample is an obvious limiting factor in this field of study. Our post hoc power calculation revealed that there was 25% power to detect a difference of 19%. A larger sample size would enable more precision around the estimate and make our data less vulnerable to confounders; however, the rate of ACR for patients suppressed less than 2 years is statistically significant. Several variables could be potentially confounding these results. Based upon our hazard ratios, only the duration of viral suppression, peak PRA I levels and total HLA mismatches appeared to significantly differ in rates of ACR. There was an increase in peak PRA I levels and a trend toward increased HLA mismatches between the groups suppressed less than 2 years compared to those suppressed more than 2 years; however, PRA I was not found to be confounding on further analysis. After controlling for HCV coinfection and HLA mismatch, a significantly higher rate of ACR was still observed in the group suppressed for less than 2 years. Posttransplant HIV and CMV viremia may also contribute to ACR; however, there were so few detected episodes in our cohort (seven detectable HIV viral loads and six episodes of CMV viremia) that an association with ACR could not be analyzed. Given such a low incidence of posttransplant HIV viremia, it is also unlikely that medication noncompliance (at least with ART) was a contributing factor to the difference in ACR. When we looked at the average tacrolimus levels at predetermined time points, we again found no difference between the two groups, making variations in immunosuppression and medication noncompliance unlikely to explain the difference in ACR between the two groups. The mechanism of immune activation in HIV infection is likely due to a combination of direct stimulation by HIV, microbial translocation, coinfections, immunosenescence and immune dysregulation (15Younas M Psomas C Reynes J Corbeau P Immune activation in the course of HIV-1 infection: Causes, phenotypes and persistence under therapy.HIV Med. 2016; 17: 89-105Crossref PubMed Scopus (97) Google Scholar). With suppressive ART, T cell activation and immune dysfunction improve, particularly during the first year of therapy, although they do not completely normalize, as shown by persistent abnormalities in markers such as IL-6, sCD-14, C-reactive protein, and IL-1β (16Hunt PW Martin JN Sinclaire E et al.T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy.J Infect Dis. 2003; 187: 1534-1543Crossref PubMed Scopus (701) Google Scholar, 17Neuhaus J Jacobs DR Baker JV et al.Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection.J Infect Dis. 2010; 201: 1788-1795Crossref PubMed Scopus (623) Google Scholar, 18Wada NI Jacobson LP Margolick JB et al.The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation.AIDS. 2015; 29: 463-471Crossref PubMed Scopus (271) Google Scholar). We postulate that the lower rate of ACR in patients with longer duration of viral suppression is the result of decreased immune activation. Alternatively, shorter durations of viral suppression prior to transplant could lead to an immune reconstitution phenomenon at the time of transplant, which could also be driving the increase rate of ACR. The CD4 at the time of transplant could also be impacting the rates of ACR. Among those suppressed for less than 2 years pretransplant, we found a significantly lower median CD4 count at the time of transplant, although there was no difference in the development of posttransplant opportunistic infections between the two groups. However, the findings by Stock and Kirk (12) suggest that immune reconstitution prior to exposure to the donor organ may actually lead to increased rates of rejection, leaving the role of immune reconstitution unclear. To further test our hypothesis and develop a pretransplant risk assessment, a prospective trial designed to look at markers of inflammation and immune activation at the time of transplant and their association with the risk of ACR is needed. Specifically, we would suggest further evaluation of the HIV latent reservoir using HIV proviral DNA, cell-associated HIV RNA levels and markers of T cell activation (CD38, HLA-DR, Ki67, CCR5, TNF-α, IL-6, hsCRP, D-dimer, cystatin C, and PD-1) (17Neuhaus J Jacobs DR Baker JV et al.Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection.J Infect Dis. 2010; 201: 1788-1795Crossref PubMed Scopus (623) Google Scholar, 18Wada NI Jacobson LP Margolick JB et al.The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation.AIDS. 2015; 29: 463-471Crossref PubMed Scopus (271) Google Scholar, 19Stock PG Barin B Hatano H et al.Reduction of HIV persistence following transplantation in HIV-infected kidney transplant recipients.Am J Transplant. 2014; 14: 1136-1141Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Such a study could have important clinical implications if results could be translated to patient selection criteria or to selection of induction therapy to optimize transplant outcomes. In conclusion, guidelines do not currently exist for the duration of viral suppression prior to transplant; however, standard practice is to recommend that patients be suppressed for 6 months prior to transplant, based upon the criteria set forth in the HIVTR study (4Stock PG Barin B Murphy B et al.Outcomes of kidney transplantation in HIV-infected recipients.N Engl J Med. 2010; 363: 2004-2014Crossref PubMed Scopus (378) Google Scholar). This criterion was established primarily to ensure that patients would be able to obtain viral suppression and to exclude patients with resistance or adherence issues. Our findings suggest that the current recommendation requiring 6 months of viral suppression prior to transplant may not be sufficient to optimize transplant outcomes; this warrants further study. At the time of the study, K.A.S. was supported by the Building Interdisciplinary Research Careers in Women's Health (BIRCWH) Program award (NIH K12 HD43489-13). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.