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1.
Comparative Study of Intravenous Immunoglobulin and Leflunomide Combination Therapy With Intravenous Immunoglobulin Single Therapy in Kidney Transplant Patients With BK Virus Infection: Single-Center Clinical Trial
Rasaei, N., Malekmakan, L., Gholamabbas, G., Abdizadeh, P.
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 2023;21(10):814-819
Abstract
OBJECTIVES Nephropathy due to BK virus infection is a major cause of graft dysfunction and loss. No specific treatment has been developed for the BK virus. Here, we compared the combination of intravenous immunoglobulin and leflunomide versus intravenous immunoglobulin to treat BK virus nephropathy after renal transplant. MATERIALS AND METHODS This study was a randomized controlled clinical trial. Sixteen kidney transplant patients with BK virus infection were randomly divided into 2 groups; 1 group received intravenous immunoglobulin, and another group received leflunomide and intravenous immunoglobulin. P < .05 was considered statistically significant. RESULTS Results of a polymerase chain reaction test for BK virus after 2 months of treatment were negative in 3 patients in the intravenous immunoglobulin group and in 7 patients in the intravenous immunoglobulin + leflunomide group. The amount of BK virus decreased significantly in each group, and a significant difference was observed between the 2 groups after 3 months (P = .014). The average level of creatinine in the intravenous immunoglobulin group at 1, 2, and 3 months after treatment was 1.7 ± 0.23, 1.8 ± 0.5, and 1.5 ± 0.3, respectively, and in the intravenous immunoglobulin + leflunomide group was 2.1 ± 0.75, 1.76 ± 0.37, and 1.4 ± 0.18, respectively (P > .05). CONCLUSIONS Although BK viral load decreased significantly in both groups, there was a significant difference between patients who received intravenous immunoglobulin versus those who received the combination of intravenous immunoglobulin + leflunomide after 3 months. The addition of leflunomide to the intravenous immunoglobulin treatment seems to have a better effect in reducing BK viral load. However, further studies with a larger sample and longer duration are needed.
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2.
Therapeutic strategies against BK polyomavirus infection in kidney transplant recipients: Systematic review and meta-analysis
Zhong, C., Chen, J., Yan, Z., Xia, R., Zeng, W., Deng, W., Xu, J., Wang, Y., Miao, Y.
Transplant immunology. 2023;:101953
Abstract
BACKGROUND The selection of antiviral therapy for BK polyomavirus (BKPyV) infection has been extensively debated. Our study aimed to assess the efficacy and safety of various treatments for BKPyV infection. METHODS We searched PubMed, EMBASE, and Web of Science databases for relevant studies regarding drug treatments for BKPyV viremia/DNAemia published between January 1, 1970 and September 30, 2022. Two independent authors screened the published studies, extracted pertinent data, and evaluated their methodological quality. A meta-analysis was performed using the RevMan software version 4.2.2. RESULTS A total of 33 published studies involving 950 patients were included in the meta-analysis. Overall, therapeutic interventions comprised immunosuppression reduction alone or in combination with leflunomide, intravenous immunoglobulin (IVIG), cidofovir, or mTOR inhibitor (mTORi) therapy. The meta-analysis revealed that the efficacy of immunosuppression reduction alone for serum BKPyV clearance was 68% (95% confidence interval [CI]: 0.58-0.77; I(2) = 78%). Moreover, the efficacy of immunosuppression reduction in combination with leflunomide, cidofovir, IVIG, or mTORi therapy for serum BKPyV clearance was 61% (95% CI: 0.47-0.74; I(2) = 83%), 71% (95% CI: 0.63-0.78; I(2) = 0), 87% (95% CI: 0.82-0.93; I(2) = 45%), and 80% (95% CI: 0.59-1.00; I(2) = 58%), respectively. Compared to immunosuppression reduction alone, immunosuppression reduction combined with IVIG therapy offered a statistically significant benefit in serum BKPyV clearance (P < 0.01) with minimal adverse reactions, whereas other adjunctive drug treatments did not demonstrate considerable effects. CONCLUSIONS Reducing immunosuppression remains the primary approach for treating BKPyV infection. Although the combination treatment with IVIG proved to be most effective, other agents might offer varied antiviral advantages of high heterogeneity, which should be substantiated in future long-term randomized controlled trials.
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3.
Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: a multicenter, prospective, randomized, double blind clinical trial
Moreso F, Crespo M, Ruiz JC, Torres A, Gutierrez-Dalmau A, Osuna A, Perello M, Pascual J, Torres IB, Redondo-Pachon D, et al
American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017;18((4):):927-935
Abstract
There are no approved treatments for chronic antibody mediated rejection (ABMR). We conducted a multicenter, prospective, randomized, placebo-controlled, double blind clinical trial to evaluate efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) (EudraCT 2010-023746-67). Patients with transplant glomerulopathy and anti-HLA donor-specific antibodies (DSA) were eligible. Patients with estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2 and/or severe interstitial fibrosis/tubular atrophy were excluded. Patients were randomized to receive IVIG (4 doses of 0.5 g/kg) and RTX (375 mg/m2 ) or a wrapped isovolumetric saline infusion. Primary efficacy variable was the decline of eGFR at one year. Secondary efficacy variables included evolution of proteinuria, renal lesions and DSA at one year. The planned sample size was 25 patients per group. During 2012-2015, twenty-five patients were randomized (13 to the treatment and 12 to the placebo group). The planned patient enrollment was not achieved because of budgetary constraints and slow patient recruitment. There were no differences between the treatment and placebo groups in eGFR decline (-4.2+/-14.4 vs. -6.6+/-12.0 mL/min/1.73 m2, p-value=0.475), increase of proteinuria (+0.9+/-2.1 vs. +0.9+/-2.1 g/day, p-value=0.378), Banff scores at one year and MFI of the immunodominant DSA. Safety was similar between groups. These data suggest that the combination of IVIG and RTX is not useful in patients displaying transplant glomerulopathy and DSA. This article is protected by copyright. All rights reserved.
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4.
Hepatitis B immunoglobulins and/or lamivudine for preventing hepatitis B recurrence after liver transplantation: a systematic review
Chen J, Yi L, Jia JD, Ma H, You H
Journal of Gastroenterology & Hepatology. 2010;25((5):):872-9.
Abstract
BACKGROUND Currently, hepatitis B immunoglobulins (HBIg) and/or lamivudine have become the main options for prevention of hepatitis B recurrence after liver transplantation. AIM: To assess the benefits of HBIg and/or lamivudine for prevention of hepatitis B recurrence after liver transplantation. METHODS We conducted a search of electronic databases and a manual search of bibliographical lists of relevant articles. All randomized clinical trials and non-randomized studies that meet the pre-specified criteria were included. However, results of non-randomized studies were reported under 'exploratory analyses' in the result section. The outcome measure was hepatitis B recurrence. RESULTS Two randomized and 44 non-randomized studies were included. Meta-analysis of two randomized studies shows one week HBIg combined with lamivudine regimen had equivalent effect compared with long-term high-dose HBIg regimen for preventing hepatitis B recurrence (RR 1.23; 95% CI 0.38-4.03; P = 0.73). For 44 non-randomized studies, only qualitative systematic review was performed. With long-term HBIg prophylaxis, hepatitis B recurrence rate ranged from 3.7% to 65%; with lamivudine prophylaxis, hepatitis B recurrence rate varied from 3.8% to 40.4%; Long-term high-dose HBIg plus lamivudine prophylaxis can reduce the risk of HBV recurrence to less than 10%. CONCLUSIONS Long-term HBIg prophylaxis or lamivudine prophylaxis can reduce the risk for hepatitis B virus recurrence. Long-term high-dose HBIg combined with lamivudine can further reduce HBV recurrence to less than 10%.
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5.
Prevention of recurrent hepatitis B virus infection after liver transplantation: hepatitis B immunoglobulin, antiviral drugs, or both? Systematic review and meta-analysis
Katz LH, Paul M, Guy DG, Tur-Kaspa R
Transplant Infectious Disease. 2010;12((4):):292-308.
Abstract
OBJECTIVES To evaluate antiviral prophylaxis against hepatitis B virus (HBV) following liver transplantation. METHODS Systematic review and meta-analysis. Clinical trials and comparative cohort studies comparing the use of hepatitis B immunoglobulin (HBIg), antivirals, or both following liver transplantation for HBV infection were included. The primary outcome was reappearance of hepatitis B surface antigen (HBsAg). Other outcomes included all-cause and HBV-related mortality, HB-related active liver disease, and reappearance of HBV DNA after transplantation. Relative risks (RR) with 95% confidence intervals (CIs) are reported. RESULTS Twenty studies (22 comparisons) were included. Ten studies compared HBIg to combination treatment, 9 compared antivirals to combination treatment, and 3 compared lamivudine (LAM) to HBIg. Combination treatment reduced HBsAg reappearance (RR 0.28; 95% CI 0.12-0.66), and was superior to HBIg alone in all other outcome measures. Combination treatment was significantly better than antivirals in preventing reappearance of HBsAg (RR 0.31; 95% CI 0.22-0.44), even when low-dose HBIg was given. No significant difference was found between HBIg and LAM monotherapy for all measured outcomes. Major limitations with regard to comparability of the study groups in non-randomized trials were revealed. CONCLUSIONS Combination treatment with HBIg and LAM reduced HBV recurrence following liver transplantation, compared with HBIg or LAM alone, and reduced mortality compared with HBIg alone.
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6.
Lamivudine or adefovir dipivoxil alone or combined with immunoglobulin for preventing hepatitis B recurrence after liver transplantation
Katz LH, Tur-Kaspa R, DG Guy, Paul M
Cochrane Database of Systematic Reviews. 2010;((7):):CD006005.
Abstract
BACKGROUND Recurrence of hepatitis B virus (HBV) infection in the liver graft is a grave complication following liver transplantation for HBV cirrhosis. Hepatitis B immunoglobulin (HBIg) seems effective in increasing survival after liver transplantation. HBIg and anti-viral drugs are given alone or in combination for its prevention. OBJECTIVES To assess the benefits and harms of different regimens for preventing HBV reactivation following liver transplantation. SEARCH STRATEGY We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until February 2010. We attempted to identify further trials by reviewing the reference lists and contacting the principal authors of identified trials. SELECTION CRITERIA Randomised clinical trials addressing benefits and harms of lamivudine or adefovir dipivoxil alone or in combination with hepatitis B immunoglobulins (HBIg) for preventing recurrent HBV infection in patients who are liver transplanted due to HBV infection with or without hepatocellular carcinoma. DATA COLLECTION AND ANALYSIS Two authors independently assessed the trials for risk of bias and extracted data. We contacted study authors whenever information was lacking. We collected information on adverse events. The primary outcomes were all-cause mortality and reappearance of hepatitis B surface antigen in serum after liver transplantation. Relative risks were calculated from individual trials. MAIN RESULTS Four trials, recruiting 136 participants, were included. Two trials compared lamivudine alone versus HBIg alone. Randomisation was performed one week after transplantation in one of the trials and after six months after transplantation in another; from transplantation until randomisation, HBIg alone was given to all patients in the two trials. A third trial compared combination treatment with lamivudine and HBIg versus lamivudine alone after one month of combination treatment, and a fourth trial compared the combination of lamivudine and HBIg versus a combination of lamivudine and adefovir dipivoxil after at least 12-month of lamivudine and HBIg combination treatment. Statistically significant differences were not detected in any of the comparisons and outcomes. All trials were open-labelled, and none of the trials were adequately powered to show a difference in HBV recurrence. No meta-analyses were performed since the identified trials assessed different comparisons. AUTHORS' CONCLUSIONS This review could not derive clear evidence from randomised clinical trials for the treatment of patients with chronic HBV following liver transplantation for preventing recurrence of HBV infection. Large randomised clinical trials comparing long-term combination treatment to each of the monotherapy alone, including the newer antiviral drugs, are needed.
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7.
The study of the different medicating ways and the formula for intravenous loading dosage of hepatitis B immunoglobulin in liver transplantation
Niu YJ, Zang YJ, Chen XG, Li W, Zhu XD, Liu Y, Wei ZY, Zhang ZT, Wang Y, Shen ZY
Zhonghua Wai Ke Za Zhi [Chinese Journal of Surgery]. 2006;44((21):):1444-7.
Abstract
OBJECTIVE To evaluate the efficacy and safety of hepatitis B immunoglobulin (HBIG) by different medicating ways in patients with liver transplantation and to explore the methods for calculating the intravenous loading dosage of HBIG. METHODS The patients enrolled were randomized into three groups (i. v group, i. m group and domino group). Under the combined utilization with Lamivudine, HBIG was given in different ways during anhepatic phase and the postoperative six days. The physical examination was done, the serum conversion rate of HBsAg was studied, the serum level of HBsAb titer, WBC, PLT, AST, GGT, TBIL, DBIL, CR, PT and PTA were tested daily within the postoperative seven days. The preoperative body weight, serum HBsAg and HBeAg titer were analyzed with the intravenous loading dosage of HBIG by multiple-factor linear regression (Stepwise). RESULTS Both the average negative-conversion rate of serum HBsAg and the average increasing rate of serum HBsAb titer are significantly faster in i. v group and domino group than that in i. m group within the postoperative four days (P < 0. 05). The regression equation to calculate the i. v loading dosage of HBIG (IU) by preoperative criteria was drawn as 1123 + 3. 4 x serum HBsAg titer (IU/L) +73 x body weight (kg). There was no linear correlation found between the level of HBeAg and the loading dosage of HBIG. There were no significant difference in body temperature, pulse rate, respiratory rate, blood pressure, WBC, PLT, AST, GGT, TBIL, DBIL, CR, PT and PTA among the three groups within the postoperative seven days (P < 0. 05). The rate of the second elevation of serum ALT was 10. 3% (3/29), 3. 4% (1/29) and 6. 7% (2/30) in i. v group, i. m group and domino group, respectively (P < 0. 05), and the rate of the local complications (sclerosis, edema, pain) at the injection site was 0, 89. 6% (26/29) and 0, respectively (P < 0. 05). CONCLUSIONS Based on the combined utilization of lamivudine and HBIG, the qualified intervention efficacy, less complications could be obtained by medicating HBIG in a domino way (i. v first, followed by i. m), which is worthy to be promoted.
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8.
A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients
Davis GL, Nelson DR, Terrault N, Pruett TL, Schiano TD, Fletcher CV, Sapan CV, Riser LN, Li Y, Whitley RJ, et al
Liver Transplantation. 2005;11((8):):941-9.
Abstract
Chronic hepatitis C is the most common indication for liver transplantation, but viral recurrence is universal and progressive graft injury occurs in most recipients. Our aim was to assess the safety, pharmacokinetics (PK), and antiviral effects of high doses of a human hepatitis C antibody enriched immune globulin product (HCIG) in patients undergoing liver transplantation for chronic hepatitis C. This was a multicenter, randomized, open-label, controlled trial conducted at 4 transplant centers in the United States. A total of 18 patients with chronic hepatitis C, who underwent liver transplantation, were randomized to receive low-dose HCIG (75 mg/kg) or high-dose HCIG (200 mg/kg), or no treatment. A total of 17 infusions of HCIG were administered in each treated patient over 14 weeks using a time-dependent dosing strategy based on the PK of anti-hepatitis B immune globulin in liver transplant recipients. Hepatitis C virus levels, liver enzymes, and liver biopsies were obtained serially throughout the study period. PK profiles of HCV antibodies were determined on days 4, 10, and 98. HCIG infusions were safe and tolerated. The infusion rate could not be maximized because of symptoms for 18% to 30% of the doses. The half-life of HCIG was extremely short immediately after transplantation but was gradually prolonged. In the high-dose group, serum alanine aminotransferase (ALT) levels normalized in most subjects and no patient developed hepatic fibrosis. However, serum HCV RNA levels were not suppressed at either dose. In conclusion, HCIG, an anti-HCV enriched immune globulin product, appears to be safe in patients with chronic hepatitis C undergoing liver transplantation. Further studies are required to determine whether the drug has beneficial effects in this group of patients.
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9.
A randomized and prospective study comparing treatment with high-dose intravenous immunoglobulin with monoclonal antibodies for rescue of kidney grafts with steroid-resistant rejection
Casadei DH, del C Rial M, Opelz G, Golberg JC, Argento JA, Greco G, Guardia OE, Haas E, Raimondi EH
Transplantation. 2001;71((1):):53-8.
Abstract
BACKGROUND The aim of this study was to compare the effectiveness of intravenous immunoglobulin (IVIg) versus monoclonal anti-CD3 as a treatment for steroid-resistant rejections. From January 1995 to June 1997, 30 patients were analyzed. They were randomized into two groups. Resistant rejections were diagnosed by core biopsy. Group A received 500 mg/ kg/day IVIg (Sandoglobulin) for 7 consecutive days, whereas group B received 5 mg/day of OKT3 for 14 consecutive days. Daily T cell CD3+ peripheral count was performed for 14 days for group B. The immunosuppression was similar for both groups. Cyclosporine was stopped during both treatments. METHODS Demographic factors, HLA mismatch, creatinine levels before and after treatment, and the incidence of rejections after treatment (up to 1 month) were taken into account for this study. RESULTS Data from different samples were compared using Fisher's exact test. Graft and patient survival were analyzed using the Kaplan-Meier method. The were no significant differences found in age, graft origin, HLA mismatch, or time of follow-up until the episode of rejection. Success was achieved for 11 (73.3%) of 15 of group A and 13 (86.6%) of 15 of group B (P=0.79). Creatinine levels before and after treatment were as follows: A, 2.99+/-1.30 mg/dl and 2.1+/-0.70 mg/dl versus B, 3.1+/-1.1 mg/dl and 2.5+/-0.8 mg/dl. Besides, we did not observe differences in the creatinine 1 month after treatment (A: 2.35+/-0.78 mg/dl; B: 2.51+/-1.10 mg/dl; P=0.66) nor in the third month (A: 1.83+/-0.58 mg/dl; B: 2.30+/-0.89 mg/dl; P=0.24). The incidence of rejections after treatment was 5 (46%) of 11 for group A and 9 (75%) of 12 for group B (P=0.4). The patient survival rates 2 years after treatment were 87 and 92% for A and B groups, respectively. Graft survival was identical (80% in both groups). CONCLUSION Should the favorable result presented in this report be confirmed in larger number of patients, IVIg could become the preferable choice of rejection treatment for steroid-resistant rejection because of a complete absence of the unwanted side effects commonly associated with OKT3.
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10.
Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation
Naoumov NV, Lopes AR, Burra P, Caccamo L, Iemmolo RM, de Man RA, Bassendine M, O'Grady JG, Portmann BC, Anschuetz G, et al
Journal of Hepatology. 2001;34((6):):888-94.
Abstract
BACKGROUND/AIMS: The long-term prophylaxis of hepatitis B after liver transplantation requires further optimization. In a randomized trial we investigated a regimen where the initially given hepatitis B immunoglobulin (HBIg) is replaced by long-term lamivudine treatment. METHODS Twenty-four liver transplant recipients (all HBsAg-positive/HBV DNA-negative before transplantation), who had received HBIg for at least 6 months without HBV recurrence, were randomized to receive lamivudine (n = 12) or HBIg (n = 12) for 52 weeks. The efficacy criteria involved seronegativity for HBsAg and undetectable HBsAg/ HBcAg in the liver. RESULTS Twenty-one of 24 patients completed the study without hepatitis B virus (HBV) recurrence (11 on HBIg, ten on lamivudine), while three patients became HBsAg-positive. Amongst those without HBV recurrence HBV DNA was detectable only by polymerase chain reaction, intermittently in serum and lymphocytes, and in liver specimens from six of eight patients receiving HBIg and five of seven receiving lamivudine. YMDD variant was found in four cases with no viral antigen expression. Eight patients continued lamivudine after the study and during an additional 6-22 months remained HBsAg-negative with normal graft function. CONCLUSIONS Substitution of HBIg with lamivudine is effective for prevention of HBV recurrence in low-risk liver transplant recipients and offers a convenient and cost-effective alternative for long-term HBV prophylaxis.