Dataset Information

Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis.

ABSTRACT:

Objective

To compare the clinical efficacy and bioequivalence of generic immunosuppressive drugs in patients with solid organ transplants.

Design

Systematic review and meta-analysis of all studies comparing generic with innovator immunosuppressive drugs.

Data sources

Medline and Embase from 1980 to September 2014.

Review methods

A literature search was performed for all studies comparing a generic to an innovator immunosuppressive drug in solid organ transplantation. Two reviewers independently extracted data and assessed quality of studies. Meta-analyses of prespecified outcomes were performed when deemed appropriate. Outcomes included patient survival, allograft survival, acute rejection, adverse events and bioequivalence.

Results

1679 citations were screened, of which 50 studies met eligibility criteria (17 randomized trials, 15 non-randomized interventional studies, and 18 observational studies). Generics were compared with Neoral (cyclosporine) (32 studies), Prograf (tacrolimus) (12 studies), and Cellcept (mycophenolate mofetil) (six studies). Pooled analysis of randomized controlled trials in patients with kidney transplants that reported bioequivalence criteria showed that Neoral (two studies) and Prograf (three studies) were not bioequivalent with generic preparations according to criteria of the European Medicines Agency. The single Cellcept trial also did not meet bioequivalence. Acute rejection was rare but did not differ between groups. For Neoral, the pooled Peto odds ratio was 1.23 (95% confidence interval 0.64 to 2.36) for kidney randomized controlled trials and 0.66 (0.40 to 1.08) for observational studies. For kidney observational studies, the pooled Peto odds ratios were 0.98 (0.37 to 2.60) for Prograf and 0.49 (0.09 to 2.56) for Cellcept. Meta-analyses for non-renal solid organ transplants were not performed because of a lack of data.There were insufficient data reported on patient or graft survival. Pooling of results was limited by inconsistent study methods and reporting of outcomes. Many studies did not report standard criteria used to determine bioequivalence. While rates of acute rejection seemed similar and were relatively rare, few studies were designed to properly compare clinical outcomes. Most studies had short follow-up times and included stable patients without a history of rejection.

Conclusions

High quality data showing bioequivalence and clinical efficacy of generic immunosuppressive drugs in patients with transplants are lacking. Given the serious consequences of rejection and allograft failure, well designed studies on bioequivalence and safety of generic immunosuppression in transplant recipients are needed.

SUBMITTER: Molnar AO

PROVIDER: S-EPMC4476317 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionPaediatric transplantation is the only curative therapeutic procedure for several end-stage rare diseases affecting different organs and body systems, causing altogether great impact in European children's health and quality of life. Transplanted children shift their primary disease to a chronic condition of immunosuppression to avoid rejection. Longer life expectancy in children poses a greater risk of prolonged and severe side effects related to long-term immunosuppressive (IS) disabilities and secondary cancer susceptibility. The goal remains to find the best combination of IS agents that optimises allograft survival by preventing acute rejection while limiting drug toxicities. This systematic review will aim to determine the optimal IS strategy within the so-called minimisation, conversion or withdrawal strategies.Methods and analysisWe will search the following databases with no language restrictions: Cochrane Central Register of Controlled Trials in the Cochrane Library, OvidSP Medline and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily; OvidSP Embase Classic+Embase; Ebsco CINAHL Plus, complete database; WHO International Clinical Trials Registry Platform search portal. We will include controlled and uncontrolled clinical trials along with any prospective or retrospective study that includes a universal cohort (all participants from a centre/region/city over a certain period). Cases series and cross-sectional studies are excluded. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. The outcomes included in this review are: patient survival, acute graft rejection, chronic graft rejection, diabetes, graft function, graft loss, chronic graft versus host disease, acute graft versus host disease, surgical complications, infusion complications, post-transplant lymphoproliferative disease, liver function, renal function, cognition, depression, health-related quality of life, hospitalisation, high blood pressure, low blood pressure, cancer-other, cancer-skin, cardiovascular disease, bacterial infection, Epstein-Barr infection, cytomegalovirus infection, other viral infections and growth.

Project description:Balancing immunosuppression to prevent rejection in solid organ transplant (SOT) recipients remains challenging. Torque teno virus (TTV), a commensal non-pathogenic virus, has been proposed as marker of functional immunity: higher loads correspond to over-immunosuppression, and lower loads to under-immunosuppression. This review offers an overview of the current evidence of the association between TTV-load and infection and rejection after SOT. A systematic literature search strategy, deposited in the PROSPERO registry, resulted in 548 records. After screening, 23 original and peer-reviewed articles were assessed investigating the association between TTV-load, infection and/or rejection in SOT. The Quality in Prognostic Studies (QUIPS)-tool was used to assess the risk of bias. Meta-analysis with random-effects was performed on results with similar outcomes and exposure measures. Most of the included studies involved retrospective cohorts in which the TTV-load was measured longitudinally, within the first 2 years post-transplantation. Infection outcomes differed between studies and included viral, bacterial, parasitic and fungal infections. Rejection was defined by biopsy confirmation or initiation of rejection treatment. Twelve out of 16 studies reported an association between high TTV-load and infections, whereas 13 out of 15 reported an association between low TTV-load and rejection. Meta-analysis showed an increased risk of infection (OR: 1.16, 95% CI: 1.03-1.32; HR: 1.05, 95% CI: 0.97-1.14) and a decreased risk of rejection (OR: 0.90, 95% CI: 0.87-0.94; HR: 0.74, 95% CI: 0.71-0.76) per 1 log TTV-load increase. The qualitative assessment showed varying risks of bias in the included studies. This systematic review and meta-analysis indicates that blood TTV-load measured within the first 2 years after SOT is associated with the risk of infection or allograft rejection, although substantial risk of bias in the studies included warrant cautious interpretation. The results in this review provide a rationale for larger, prospective, studies into TTV as marker of infection and rejection after SOT.

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