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3106 23. Ekberg H, Tedesco-Silva H, Demirbas A et al. For the ELITE–Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357: 2562–2575 24. Ekberg H, Grinyó J, Nashan B et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR Study. Am J Transplant 2007; 7: 560–570 25. International Neoral Renal Transplantation Study Group. Cyclosporine microemulsion (Neoral) absorption profiling and sparse-sample predictors during the first 3 months after renal transplantation. Am J Transplant 2002; 2: 148–156 26. Marquet P. Clinical application of population pharmacokinetic methods developed for immunosuppressive drugs. Ther Drug Monit 2005; 27: 727–732 27. Le Meur Y, Büchler M, Thierry A et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant 2007; 7: 2496–2503 28. Zucker K, Rosen A, Tsaroucha A et al. Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate mofetil in combination therapy, and analogous in vitro findings. Transpl Immunol 1997; 5: 225–232 L. Landin et al. 29. Hubner GI, Eismann R, Sziegoleit W. Drug interaction between mycophenolate mofetil and tacrolimus detectable within therapeutic mycophenolic acid monitoring in renal transplant patients. Ther Drug Monit 1999; 21: 536–539 30. Picard N, Premaud A, Rousseau A, Le Meur Y, Marquet P. A comparison of the effect of ciclosporin and sirolimus on the pharmacokinetics of mycophenolate in renal transplant patients. Br J Clin Pharmacol 2006; 62: 477–484 31. Smak Gregoor P, van Gelder T, Hesse CJ, van der Mast BJ, van Besouw NM, Weimar W. Mycophenolic acid plasma concentrations in kidney allograft recipients with or without cyclosporin: a crosssectional study. Nephrol Dial Transplant 1999; 14: 706–708 32. Kobayashi M, Saitoh H, Tadano K, Takahashi Y, Hirano T. Cyclosporin A, but not tacrolimus, inhibits the biliary excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistance-associated protein 2 in rats. J Pharmacol Exp Ther 2004; 309: 1029–1036 33. Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int 2002; 62: 311–318 Received for publication: 7.10.09; Accepted in revised form: 19.2.10 Nephrol Dial Transplant (2010) 25: 3106–3115 doi: 10.1093/ndt/gfq125 Advance Access publication 11 March 2010 Kidney transplants in HIV-positive recipients under HAART. A comprehensive review and meta-analysis of 12 series Luis Landin1, Jose C. Rodriguez-Perez2, Miguel A. Garcia-Bello2, Pedro C. Cavadas1, Alessandro Thione1, Peter Nthumba3, Marino Blanes4 and Javier Ibañez1 Transplant Surgery Division, University Hospital “La Fe”, Av. Campanar 21, 46009 Valencia, Spain, 2Nephrology Division, Dr. Negrín University Hospital of Gran Canaria, Plaza Barranco De La Ballena S/N, 35012 Las Palmas De Gran Canaria, Spain, 3Clinical Fellow, Clinica Cavadas, Pedro Cavadas Foundation and AIC Kijabe Hospital P.O. Box 20, Kijabe 00220, Kenya and 4Infectious Disease Division, University Hospital “La Fe”, Av. Campanar 21, 46009 Valencia, Spain 1 Correspondence and offprint requests to: Luis Landin; E-mail: [email protected] Abstract Background. Kidney transplantation is being introduced gradually for the treatment of end-stage renal disease in patients who are human immunodeficiency virus (HIV) positive. Our aim was to review the outcomes of kidney transplantation in HIV-positive recipients who were being treated with highly active antiretroviral therapy (HAART). Methods. Eligible papers were English language manuscripts, published between July 2003 and April 2009 and available through Medline, that described three or more recipients of kidney transplants who were HIV positive and undergoing HAART. The regimens for induction and maintenance therapy, organ rejection, patient survival, CD4 counts, HIV progression, infectious complications and deaths were recorded. The survival at 1 year, organ rejec- tion and infectious complications were evaluated using a random effects model with 95% confidence intervals (CI). Results. Twelve case series met the defined criteria. Induction therapy consisted most commonly of the administration of anti-CD25 monoclonal antibodies, and triple immunosuppressive therapy was used most commonly for maintenance. Among the 254 patients, 1-year survival was 0.93 (95% CI, 0.90–0.96), organ rejection was diagnosed in 0.36 (95% CI, 0.25–0.49) and infectious complications occurred in 0.29 (95% CI, 0.17–0.43). The CD4 counts decreased after transplantation but recovered later. Acquired immune deficiency syndrome (AIDS)-defining infections occurred in three patients. Conclusions. Kidney transplantation appears to be safe in patients undergoing HAART. However, larger series of pa- © The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: [email protected] Kidney transplants in HIV-positive recipients under HAART tients are needed to determine the best protocols for the induction and maintenance of immunosuppression. Keywords: HAART; HIV; kidney transplantation; review Abbreviations: AIDS: acquired immune deficiency syndrome; AIN: anal intraepithelial neoplasia; ATG: anti-thymocyte globulin; CI: confidence interval; CMV: cytomegalovirus; CsA: cyclosporine A; EBV: Epstein–Barr virus; HAART: highly active antiretroviral therapy; HIV: human immunodeficiency virus; HIVAN: HIV-associated nephropathy; HPV: human papillomavirus; MMF: mycophenolate mofetil; PTLD: post-transplant lymphoproliferative disease Introduction Only a decade ago, seropositivity for human immunodeficiency virus (HIV) was considered to be an absolute contraindication for organ transplantation. In recent years, however, the use of highly active antiretroviral therapy (HAART) for the treatment of infection with HIV has led to a considerable increase in life expectancy. Kidney transplantation has emerged as a feasible treatment option for chronic renal failure caused by HIV-associated nephropathy (HIVAN) [1] in this group of patients. Our aim was to identify and review published case series that described kidney transplantation in HIV-positive recipients who received HAART, and to evaluate their outcomes. Materials and methods The papers eligible for this study were manuscripts published in the English language between July 2003 and April 2009 that were available through Medline. The selected papers each described three or more kidney transplants in HIV-positive recipients that were already under HAART. The data that were collected included the aim of each study, the inclusion and exclusion criteria, the type of HAART regimen, the sample size, the induction and maintenance therapy, and the rates, causes and treatment of episodes of rejection and return to dialysis. Rates of survival of the graft and patient, infectious complications, and deaths were calculated as the number of events divided by the total sample size. If additional outcome data were reported, they were also included in the analysis. A meta-analysis of single proportions using the Freeman–Tukey double arcsine transformation was performed [2,3]. The transformed data were combined to estimate the pooled percentages with 95% confidence intervals using a random effects model [4]. We assessed the heterogeneity among studies using the Cochran Q test (χ2n−1; P < 0.05 to denote statistical significance) and estimated the amount of variation by I2 [5]. Statistical sources of heterogeneity were explored by examining the relationship between one or more study-level characteristics and the effect sizes that were observed in the studies using weighted least squares meta-regression. A rank correlation test of funnel plot asymmetry (z) was used to assess the presence of publication bias. Data analysis and visualization were performed using the R statistical software package (R Development Core Team, Vienna, Austria; URL: http://www.R-project.org; version 2.9.0), using the software libraries ‘meta’ [6] and ‘metafor’ [7], for the meta-analysis and meta-regression models, respectively. Results A total of 12 eligible published case series were identified. These are summarized in Tables 1–4. The results of the 3107 analysis of survival, rejection and complications due to infection are shown in Figures 1–3. The first clinical study published was a pilot study of safety and efficacy reported by Stock et al. [8]. The inclusion criteria were undetectable HIV infection for 3 months, CD4 count >200/μL, no history of opportunistic infections and stable antiretroviral therapy for 3 months. The authors followed up 10 patients for 480 days, with a survival rate of 100%. Rejection occurred in 50% of the patients, and anti-thymocyte globulin (ATG) was used to treat episodes of rejection that were resistant to steroids. Infectious complications occurred in two of the recipients who were treated with ATG (n = 3), whereas three such episodes were reported in those who did not receive ATG (n = 7). The CD4 counts were not affected greatly by the immunosuppressive (IS) therapy, except in the recipients who were treated with ATG. Anal infection with human papillomavirus (HPV), with progression to anal intraepithelial neoplasia (AIN), occurred in 44% of the patients. No acquired immune deficiency syndrome (AIDS)-defining infection or anal cancer was observed. Maintenance of blood levels of cyclosporine A (CsA) was difficult because of interactions with HAART protease inhibitors. The authors concluded that it was safe to perform kidney transplantation in HIV-positive recipients under HAART, although high rates of rejection should be expected. Roland published the findings of a continuation of the same series, which included 26 patients [9]. The rate of rejection was reduced to 38%, but graft loss occurred in 12% of the recipients. A death rate of 7%, which could be attributed to episodes of bowel ischaemia and staphylococcal sepsis, was reported. The author concluded that a multidisciplinary team was necessary to manage the required pharmacokinetic changes and adjustment of drugs successfully. Abbott and collaborators performed a retrospective analysis of the 2002 United States Renal Data System (USRDS) [10]. They assessed information on graft loss, patient survival, rates of rejection and immunosuppressive therapy in 47 HIV-positive recipients of kidney transplants. However, they did not describe patient management, CD4 counts and HIV progression, complications due to infection, and causes of death. The authors found that the risk of death for recipients who were infected with HIV was lower than for recipients who were HIV negative, but that the differences were not statistically significant (P = 0.31). This study was excluded from our analysis of complications due to infection because of lack of data. Tan et al. compared two short case series of kidney transplants from living, related donors (LRD, n = 3) or deceased donors (DD, n = 4) in HIV-positive recipients. The LRD group received induction therapy with alemtuzumab and tacrolimus monotherapy (tolerogenic regimen) whereas the DD group did not receive induction therapy, and triple standard therapy was used to maintain immunosuppression. The rate of graft survival was 100% in the LRD group, whereas the incidence of rejection, CD4 counts post-transplant and HIV viral load were considerably higher in the DD group. No infections that define AIDS occurred in either group, but one case of plantar fasciitis and one case of basal cell carcinoma were diagnosed in 3108 L. Landin et al. Table 1. Brief description of reports Reference Aim Inclusion criteria Exclusion criteria HAART regimen Stock et al. [8] Prospectively evaluate safety and efficacy Undetectable HIV for 3 months CD4 ≥200/μL (kidney) No history of OI Stable ARV for 3 months AIDS-defining OI History of cancer except BCC/AIN Varied HCV ± in kidney patients with cirrhosis on liver biopsy Elevated HIV RNA History of neoplasm or OI Altered mental status Progressive multifocal leukoencephalopathy MAC disease History of Pneumocystis jiroveci, CMV disease and Kaposi's sarcoma Not specified Not specified Undetectable HIV CD4 ≥200/μL Not specified Varied Adherence to HAART and dialysis Undetectable HIV CD4 ≥200/μL Not specified Not specified Varied Not specified Not specified History of cancer except BCC, cutaneous KS, AIN Prior transplant Pregnancy Wasting HCV ± in kidney patients with cirrhosis on liver biopsy Chronic intestinal cryptosporidiosis Progressive multifocal leukoencephalopathy Resistant fungal infections History of AIDS-defining infection Drug abuse Varied Roland [9] Prospectively describe safety and efficacy Undetectable HIV for 3 months CD4 ≥200/μL (kidney) No history of OI Abbott et al. [10] Retrospectively analyse the USRDS database to 2002 Retrospectively evaluate a tolerogenic protocol in HIV-positive recipients Prospectively determine safety of kidney transplantation as an alternative to haemodialysis Retrospectively compare pairs of kidneys from the same donor transplanted to HIV-positive and HIV-negative patients from UNOS Renal Transplant Registry Prospectively assess the use of ATG in reversing rejection Not specified Mazuecos et al. [15] Retrospective outcome analysis Trullas et al. [16] Prospectively evaluate the safety of lymphocyte depletion (ATG) Roland et al. [17] Prospectively assess outcomes Undetectable HIV for 3 months CD4 ≥200/μL for 6 months Stable ARV for 3 months Undetectable HIV for 3 months CD4 ≥200/μL for 6 months Allowed TBC, Candida oesophagitis and P.jiroveci Undetectable HIV for 3 months Tan et al. [11] Kumar et al. [12] Qiu et al. [13] Carter et al. [14] Undetectable HIV for 3 months CD4 ≥200/μL No history of OI Stable ARV for 3 months CD4 ≥200/μL for 6 months Gruber et al. [18] Retrospectively assess outcomes Gasser et al. [19] Prospectively evaluate anti-herpes viral immunity after ATG induction Stable HAART Undetectable HIV for 3 months CD4 ≥200/μL (kidney) Undetectable HIV for 6 months CD4 ≥200/μL (kidney) Not specified Varied Not specified Varied AIDS-defining OI (except Candida oesophagitis) Varied (zidovudine and stavudine avoided) Chronic intestinal cryptosporidiosis Progressive multifocal leukoencephalopathy Lymphoma Visceral KS History of OI or neoplasm Use of IL-2 or GM-CSF Pregnancy Wasting Prior organ transplantation Varied Varied HIV, human immunodeficiency virus; RNA, ribonucleic acid; OI, opportunistic infections; ARV, antiretroviral agents; BCC, basal cell carcinoma; AIN, anal intraepithelial neoplasia; HCV, hepatitis C virus; CsA, cyclosporine A; MMF, mycophenolate mofetil; Sir, sirolimus; KS, Kaposi's sarcoma; CNI, calcineurin inhibitor; MAC, Mycobacterium avium complex; TBC, tuberculosis; AZA, azathioprine; USRDS, United States Renal Data System; HAART, highly active antiretroviral therapy; ATG, anti-thymocyte globulin; UNOS, United Network for Organ Sharing. Kidney transplants in HIV-positive recipients under HAART 3109 Table 2. Immunosuppression and rejection Reference n Induction Maintenance Stock et al. [8] 10 Not used Roland [9] 26 Not specified Abbott et al. [10] 47 Anti-CD25 (46%) Tan et al. [11] 7 None (42%) (deceased donor) Alemtuzumab (57%) (living-related donor) CsA/Sir MMF Steroids Steroids CsA MMF CsA MMF Tac AZA Triple therapy Tac monotherapy Kumar et al. [12] 40 100% Anti-CD25 Qiu et al. [13] 38 60% anti-CD25 Carter et al. [14] 20 55% anti-CD25 Mazuecos et al. [15] 10 Trullas et al. [16] 3 Roland et al. [17] 18 40% ATG (1) Anti-CD25 (3) 100% ATG (3) Sir (2) Tac (1) 39% anti-CD25 Gruber et al. [18] 8 100% anti-CD25 Gasser et al. [19] 27 37% ATG 40% anti-CD25 Steroids CsA Sir CsA (53%) Tac (34%) Sir (37%) Steroid-sparing (2.6%) MMF Steroids CsA/Tac/Sir Steroids Tac MMF MMF Steroids Steroids CNI ± MMF MMF CsA Steroids CsA or Tac MMF or AZA Steroids Cause of rejection (n) Return to dialysis (%) Treatment of rejection Not specified 0% CsA→Tac ATG (AMR) Not specified 12% Not specified Not specified 2% Not specified Non-compliance (3) 50% None 0% Subtherapeutic IS levels (3) Non-compliance (2) 10% Not specified Mpred (250 mg) Rituximab (for AMR) Not specified Not specified 10% Steroids ± ATG (7) Steroids Not specified 10% Mpred Plasmapheresis ± ↑Tac (1) Not specified 0% Not specified Not specified 11% CsA→Tac ATG Not specified 12.5% Mpred ATG Not specified 0% Not specified Rejection rates are % of recipients that suffered rejection, as published.OI, opportunistic infections; CsA→Tac, switch from cyclosporine A to tacrolimus; Sir, sirolimus; ATG, anti-thymocyte globulin; CsA, cyclosporine A; MMF, mycophenolate mofetil; AZA, azathioprine; AMR, antibody mediated rejection; Mpred, methylprednisolone; Tac, tacrolimus; IS, immunusuppression. the DD group. The authors concluded that a tolerogenic regimen in HIV-positive recipients could be safe and effective [11]. For statistical analysis, this study was split into two groups on the basis of well-defined criteria. Kumar et al. reported on the largest series of kidney transplants in HIV-positive recipients that has been conducted so far [12]. Forty HIV-positive recipients received induction therapy with anti-CD25 monoclonal antibodies (basiliximab), whereas maintenance was based on CsA, sirolimus and prednisone. Antibody-mediated rejection that was resistant to steroids was treated by lymphocyte depletion with rituximab. The authors reported that 17.5% patients died after 2 years. There were no cases of infections that define AIDS, but the authors did not specify whether patients treated with rituximab suffered more complications due to infection than those who did not receive rituximab. The plasma levels of HIV-1 remained undetectable, and the CD4 counts remained >400/μL. The authors concluded that positive HIV status should not be considered a contraindication for kidney transplantation. A report from the Terasaki Foundation, which used the data available through the United Network for Organ Sharing (UNOS) Renal Transplant Registry, compared the outcomes of transplantation of 38 pairs of kidneys retrospectively. One kidney from each donor was transplanted into an HIV-positive recipient and the other into an HIVnegative recipient [13]. The database did not provide specific information for the HIV-positive recipients, such as the use of HAART or the inclusion criteria. The authors concluded that they did not observe a difference between the survival rates of HIV-positive and HIV-negative recipients who received transplants from the same donor (91.3% vs 87.3% after 5 years, P = 0.72). Carter et al. evaluated 20 patients prospectively, of whom 11 received induction therapy with anti-CD25 anti- 3110 L. Landin et al. Table 3. Follow-up and outcomes Reference Lowest post-transplant Follow-up days [mean ± Graft survival (days Patient survival (days Cr mg/dL (mean ± SD SD or median (range)] mean ± SD or %) mean ± SD or %) or median) Death Causes of death Stock et al. [8] Roland [9] 480 ± 300 314 (3–1696) 100% 88% 480 ± 300 (100%) 92% 1.6 ± 0.49 Not specified 0% 8% Abbott et al. [10] Tan et al. [11] 98%* 25% 100% 75% 95.7% 1485 ± 425 (100%) 246 ± 87 (100%) 632 ± 227 (82.5%) Not specified 1.48 ± 0.21 1.45 ± 0.23 2.0 4.3% 0% Kumar et al. [12] 956 ± 481 1485 ± 425 246 ± 87 730 Qiu et al. [13] 1825 76% 89% 1.8 ± 0.2 Carter et al. [14] Mazuecos et al. [15] Trullas et al. [16] Roland et al. [17] 854 489 ± 468 720 ± 180 1520 ± 593 90% 90% 100% 1263 ± 718 (83%) 95% 489 ± 468 (100%) 720 ± 180 (100%) 1520 ± 593 (77%) Not specified 1.5 ± 0.5 1.48 ± 1 1.1 Gruber et al. [18] Gasser et al. [19] 450 (240–1410) 360 88% 100 450 (100%) 100% 1.2 Not specified bodies and seven were given ATG to treat acute rejection [14]. There were no statistically significant differences in survival without rejection with respect to the administration of anti-CD25 (36% in the anti-CD25 group vs 66% in the non-anti-CD25 group, P = 0.759). Twelve infectious complications, one AIDS-defining infection and one death occurred in the ATG group, in contrast to two complications due to infection and no deaths in the non-ATG group. The report did not specify whether these adverse outcomes occurred in patients who had also undergone anti-CD25 induction. The CD4 counts at the end of the follow-up period were >250/μL. The HIV viral load increased in four patients. The authors reported that this was due to noncompliance with therapy (n = 1) or before HAART therapy was resumed (n = 3). They concluded that ATG should be used with caution to treat rejection in this population. Two reports from Spain present favourable results for kidney transplantation in HIV-positive recipients. Mazuecos et al. reported their early experience of kidney transplantation after the introduction of HAART; their series started in 2001. None of the recipients developed AIDS, but 40% showed pharmacokinetic changes. Rejection was observed in 40% of the recipients but was controlled Ischaemic bowel episode (1) Staphylococcal sepsis (1) Not specified 17.5% Pulmonary embolism (1) Anaphylactic reaction to drug (1) Gastrointestinal bleeding (1) Sepsis (1) Chest infection (2) Necrotizing fasciitis (1) Infection of lymphocoele (1) Myocardial infarction (1) 10% Bacterial pneumonia (1) Gastrointestinal haemorrhage (1) Respiratory failure (2) 5% Heart failure (1) 0% 0% 22% Heart failure (1) Pulmonary fibrosis (1) Respiratory failure–myocardial infarction (1) Unknown cause (1) 0% 0% successfully in all cases. The level of HIV and the CD4 counts remained stable after transplantation, and the authors concluded that kidney transplantation was safe in HIV-positive recipients under HAART [15]. Trullas et al. reported a case series of three HIV-positive recipients who underwent lymphocyte depletion with ATG. In their study, they compared them with a group of HIV-negative recipients. After a median follow-up period of 720 days, no viral or opportunistic infections had occurred, and the mean CD4 count was 235/μL. They concluded that the use of ATG was as safe in HIV-positive as in non-HIV-infected recipients [16]. Roland et al. reported a prospective evaluation of the outcome of kidney transplantation in a cohort of 18 recipients [17]. Induction therapy with anti-CD25 monoclonal antibodies was used in 39% of the recipients, and ATG was used to treat rejection. The patients who received induction therapy with anti-CD25 did not suffer from more opportunistic infections than patients who did not receive this therapy. However, one patient died during the first year of follow-up. The authors concluded that larger studies could facilitate the identification of potential predictors of poor outcome. Not specified ≥300 ≥500 235 ± 67 Not specified ≥200 Not specified 589 ± 313 946 ± 800 ≥200 ≥200 ATG recipients 475 (237–890) Non-ATG recipients 443 (334–734) ≥200 606 ± 37 439 (293–613) ≥200 483 (108–1843) Roland [9] Abbott et al. [10] Tan et al. [11] Qiu et al. [13] Carter et al. [14] Mazuecos et al. [15] Trullas et al. [16] Roland et al. [17] Gruber et al. [18] Gasser et al. [19] 517 (anti-CD25) 302 (ATG) 670 ± 481 436 (3–975) Not specified Undetectable Detectable in 30% Detectable in 39% Detectable in 20% Not specified Detectable in 20% Not specified 1481 ± 2862 50 ± 0 Detectable in 10% Detectable in unknown % Undetectable HIV load post-transplant Not specified Yes No Yes Yes Not specified Not specified Yes Not specified Yes Yes Yes Pharmacokinetic changes Staphylococcus aureus wound infection (2) Haemophilus influenza bacterial pneumonia (1) S.aureus endocarditis (1) Pseudomonas aeruginosa sepsis (1) Staphylococcal sepsis (1) Candida oesophagitis (1) Not specified Plantar fasciitis (1) None Sepsis (1) Chest infection (2) Necrotizing fasciitis (1) Infection of lymphocoele (1) Admitted urinary tract infection (9) Bacterial pneumonia (1) Candida oesophagitis (1) S.aureus endocarditis with septic embolization (1) Streptococcus viridans bacteraemia (1) Pseudomonas pneumonia with multi-organ failure (1) Escherichia coli urosepsis (1) Culture-negative urosepsis (1) Enterococcus bacteraemia (1) Polymicrobial pneumonia sepsis (1) Clostridium difficile colitis (1) Diverticulitis and secondary bacterial peritonitis (1) Influenza, bacterial pneumonia (1) Pseudomonas pneumonia (1) Pneumonia (3) VZV (1) Urinary tract infection (1) CMV (1) Candida oesophagitis (1) CMV (1) Pneumonia (1) Urinary tract infection (3) 42.8% CMV (ATG) 80% EBV reactivation (ATG) 11.1% CMV (anti-CD25) 6.7% EBV reactivation (anti-CD25) Infectious complications (n) Not specified Not specified Not specified Not specified Not specified Not specified Not specified Not specified BCC None Not specified Not observed Post-transplant neoplasia Not specified Not specified Not specified Not specified Not specified Not specified Not specified Not specified Not specified Not specified Not specified 44% Progression of AIN Tx, transplant; SD, standard deviation; HIV, human immunodeficiency virus; HPV, human papillomavirus; BCC, basal cell carcinoma; VZV, varicella zoster virus; AIN, anal intraepithelial neoplasia; ATG, antithymocyte globulin; EBV, Epstein-Barr virus. Kumar et al. [12] Not specified 424 ± 384 76 ± 58 ≥400 441 (200–1054) Stock et al. [8] 419 ± 287 423 ± 93 Reference Mean CD4 counts post-Tx (cells/μL) or median (range) Mean CD4 counts pre-Tx ± SD (cells/μL) or median (range) Table 4. HIV and related complications Kidney transplants in HIV-positive recipients under HAART 3111 3112 L. Landin et al. Fig. 1. Pooled estimated proportion of patients surviving the first year, analysed using a random effects model. Fig. 2. Pooled estimated proportion of patients suffering organ rejection, analysed using a random effects model. Fig. 3. Pooled estimated proportion of patients suffering complications due to infection, analysed using a random effects model. Gruber et al. reported a retrospective evaluation of kidney transplants in eight patients after anti-CD25 induction, followed by triple therapy. One graft loss had occurred after a median follow-up period of 15 months. The incidence of rejection remained low (12.5%). The authors maintained high trough levels of CsA and monitored the blood for mycophenolate mofetil (MMF). Only one episode of infection with cytomegalovirus (CMV) occurred under this Kidney transplants in HIV-positive recipients under HAART regimen. The authors suggested that this protocol was safe for selected HIV-positive recipients of kidney transplants who were given HAART [18]. A recent prospective study by Gasser et al. evaluated the effect of ATG induction therapy on immunity against herpes viruses in HIV-positive recipients of kidney allografts [19]. The authors found that treatment with ATG had a devastating effect on the functionality of T cells. A high rate of reactivation of CMV was observed in the ATG group (n = 7) as compared to the non-ATG group (n = 11) (42% vs 11%, P = 0.26), but this did not affect the specific T-cell response to CMV which was present in 92% of CMVinfected patients (n = 25). They observed an almost complete absence of functional responses in ATG-treated recipients compared to ATG-untreated individuals, including Epstein–Barr virus (EBV)-specific CD8+ T-cell immune responses (P < 0.001). Reactivation of EBV occurred in 80% of the patients in the ATG group. However, at follow-up (after 1 year), no post-transplant lymphoproliferative disease (PTLD) was observed. The HIV-specific CD8+ lymphocyte response was affected by ATG in comparison with patients who did not receive ATG (P < 0.05). The authors concluded that non-depleting regimens were preferable in HIV-positive recipients of transplants. The analyses of survival and rejection included 254 patients, and the analysis of complications due to infection included 207 patients. Of the 254 patients, 238 survived; this gave a pooled estimate of the percentage survival in the first year of 0.93 (95% CI, 0.90–0.96) (Figure 1). Analysis using the Q statistic revealed that there was no evidence of heterogeneity (Q(12) = 9.58; P < 0.653; I2 = 0; 95% CI, 0–0.45). A total of 78 episodes of rejection were found among the patients (0.36; 95% CI, 0.25–0.49) (Figure 2), and the differences among studies could be attributed to variations in the true magnitude of this parameter from study to study (Q(12) = 46.8, P < 0.0001; I2 = 0.74; 95% CI, 0.55–0.85). However, these differences in the rates of rejection could not be explained by the data retrieved. Fifty-two incidents of infectious complications were observed (0.29; 95% CI, 0.17–0.43) (Figure 3), and there was strong evidence of substantial heterogeneity (Q(11) = 47.73, P < 0.0001; I2 = 0.77; 95% CI, 0.59–0.86). However, the differences in the incidence of complications due to infection could not be explained by other reported variables. The degree of publication bias was not statistically significant (z = 0.86, P = 0.39 for survival; z = 1.47, P = 0.14 for rejection; z = 0.83, P = 0.4 for complications due to infection). Discussion Before the development of HAART, the life expectancy of HIV-positive patients was considerably shorter than at present, and there was concern regarding the progression of HIV, the development of opportunistic infections and the risk of neoplastic complications (e.g. Kaposi's sarcoma) after organ transplantation. Nowadays, life expectancy has increased to the point where HIVAN is a common cause of renal dysfunction [1], and renal replacement is being considered for the treatment of these patients [20]. 3113 Stock et al. defined the selection criteria for proceeding with kidney transplantation [8]. These criteria have been used in most of the case series published thereafter. One of the major concerns with regard to organ transplantation into an HIV-positive recipient is the impact that IS therapy can have on survival. In this review, the patient survival rate within the first year of transplantation was 93%, whereas the graft survival rate was somewhat lower (87%). The meta-analysis showed that the rate of survival was homogeneous among studies; hence, the results may reflect the true outcomes. These data were similar to those published in the 2006 Organ Procurement and Transplantation Network (OPTN)/Scientific Registry of Transplant Recipients (SRTR) Annual Report, in which survival of kidneys from non-expanded criteria donors was 91% at 1 year [21]. With regard to rejection, most studies have observed a higher number of rejections among HIV-positive recipients than among HIV-negative recipients at their institutions; however, no statistical confirmation was provided. The mean rate of organ rejection was 36%, but the rate of return to dialysis was generally <12%. These results suggest that HIV-positive patients can still raise an immunological response to allografted tissue while receiving certain types of treatment (namely HAART) [8], and that the physician should be ready to treat episodes of rejection. A critical point for transplantation is the selection of the optimal prophylaxis protocol to prevent rejection, which requires the modulation of the immune system in a HIVpositive patient, who already has immunological dysfunction. The most frequent induction therapy consisted of treatment with anti-CD25 monoclonal antibodies. Maintenance IS therapy consisted most commonly of triple therapy with a calcineurin inhibitor (CNI) (CsA is the most frequently used), MMF and steroids. Unfortunately, our meta-regression analysis could not clarify whether such protocols influence the number or type of complications that are due to infection. In the series of 40 patients described by Kumar et al., anti-CD25 and triple therapy were utilized, and 14 infections were reported; two of the infections resulted in death [12]. In contrast, Tan et al. showed a decrease in CD4 levels from 946 to 76 counts/μL after the administration of alemtuzumab–tacrolimus, with 100% survival of patients and grafts, and no complications due to infection or death [11]. Rejection was treated most commonly with steroid boluses that controlled rejection successfully. When ATG was used to treat steroid-resistant acute rejection, a number of complications due to infection were observed, as in the series reported by Roland [17]. Changes in drug pharmacokinetics were reported in most of the series, as a result of the use of protease inhibitors, and they were managed successfully. However, a few episodes of rejection were observed [12]. Lymphocyte depletion was associated with the rates of reactivation of CMV and EBV of 42% and 80%, respectively, in the series reported by Gasser [19]. Carter found that the ATG group (n = 11) suffered 10 incidents of infectious complications, in contrast to the non-ATG group (n = 9), who suffered only two such incidents. Overall, the number of deaths associated with infections (n = 6) was fewer than the number ascribed to non-infec- 3114 tious causes (n = 14), which contradicts the belief that complications due to infection may be a more frequent cause of death after transplantation in HIV-positive recipients than in uninfected recipients. The HIV viral load was detectable in most case series after transplantation, although the CD4 counts were >200/μL in most patients. However, these data were not always available, as shown in Table 4. Differences in the rate of occurrence of infectious complications might be explained by differences among the studies, but none of the variables included in the series could explain such differences. The incidence of post-transplant neoplasia was low: a single case of basal cell carcinoma was reported [11]. AIN was evaluated only by Stock et al. [8], who showed a rate of progression of 44%, but no other series included information about this parameter. This review has some limitations that deserve attention. A limiting factor of this meta-analysis is that manuscript search was performed in Medline database only. Unpublished data were not obtained, which may have led to the omission of relevant information, including data on harmful outcomes. Key design features of the different studies were described incompletely, and many outcomes were not reported by all trials. Most of the collected data were descriptive and obtained from retrospective studies that lacked control groups, and the authors commonly compared them against experience with other patients at their institutions. Some researchers published case series that comprised only a small sample of patients with a shortterm follow-up [11,16]. Some authors did report 1-, 3- or 5-year follow-up periods, but unfortunately, the data were presented in figures or summarized, and therefore could not be formatted for analysis. Other studies lacked data on complications due to infection [10]. More importantly, some studies did not clarify the differences between patients who were treated with ATG and those who were not, which precluded statistical analysis [14,19]. These case series may not be a random selection of all available data because the likelihood for publication bias for favourable outcomes may have prompted optimistic conclusions; however, this was not statistically supported by the publication bias analysis. With respect to heterogeneity, the pooled estimates that relate to rejection and complications due to infection should be treated with caution. The extent of heterogeneity in a meta-analysis partly determines how difficult it is to draw general conclusions. For that reason, the true incidence of rejection and complications due to infection varied with the type of study. Although the heterogeneity was explored, the variables that explain the differences among the studies remained unknown. Therefore, it appears that our sample was a good representation of all types of studies of kidney transplantation in patients with HIV infection, even though conclusions of null moderating effects may be incorrect, due to the low power of the analysis. Conclusions The results presented in this review support the treatment of end-stage renal disease in HIV-positive recipients by renal L. Landin et al. transplantation. Good rates of patient survival were observed, although organ rejection occurred frequently. HIV-positive transplant recipients were cared for by multidisciplinary teams, in order to control the pharmacokinetic variations. Opportunistic infections, neoplasia and HIV reactivation were uncommon, although some authors found that lymphocyte depletion increased the risk of reactivation of CMV and EBV. These findings emphasize the need for a clinical trial to compare the safety of different IS protocols. A prospective multi-centre evaluation of kidney transplantation in HIV-positive recipients is currently underway (www.hivtransplant.com). The results of this review show that HIV infection can no longer be considered a contraindication for renal transplantation, but further studies are required to identify the optimal choice of IS therapy in this group of patients. Conflict of interest statement. None declared. References 1. Winston JA, Bruggeman LA, Ross MD et al. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. N Engl J Med 2001; 344: 1979–1984 2. Freeman MF, Tukey JW. Transformations related to the angular and the square root. Ann Math Statist 1950; 21: 607–611 3. Miller JJ. The inverse of the Freeman–Tukey double arcsine transformation. Am Stat 1978; 32: 138 4. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188 5. Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. 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