Transition from Antigenemia to Quantitative Nucleic Acid Amplification Testing in Kidney Transplant Recipients Receiving Preemptive Therapy for Cytomegalovirus Infection.

Due to the high costs, the strategy to reduce the impact of cytomegalovirus (CMV) after kidney transplant (KT) involves preemptive treatment in low and middle-income countries. Thus, this retrospective cohort study compared the performance of antigenemia transitioned to quantitative nucleic acid amplification testing, RT-PCR, in KT recipients receiving preemptive treatment as a strategy to prevent CMV infection. Between 2016 and 2018, 363 patients were enrolled and received preemptive treatment based on antigenemia (n=177) or RT-PCR (n=186). The primary outcome was CMV infection or disease. There were no differences in one-year cumulative incidence of CMV-related events (50.8% vs. 44.1%, P=0.20), neither in time to diagnosis (47.0 vs. 47.0 days) among patients conducted by antigenemia vs. RT-PCR, respectively. The length of CMV first treatment was longer with RT-PCR (20.0 vs. 27.5 days, P<0.001), while the rate of retreatment was not different (14.7% vs. 11.8%, P=0.48). In the Cox regression, the variables associated with CMV-related events were acute rejection within 30 days (HR=2.05, p=0.01) and 30-day glomerular filtration rate (HR=0.98, p<0.001). In conclusion, acute rejection and glomerular filtration rate are risk factors for CMV infection and disease, showing comparable performance in the impact of CMV-related events between antigenemia and RT-PCR for preemptive treatment.

Use of Preemptive Treatment for Immune Thrombotic Thrombocytopenic Purpura: A Matched Survival Analysis

Background: Immune Thrombotic thrombocytopenic purpura (iTTP) is a relapsing disorder, resulting from depletion of ADAMTS13. With the goal of preventing clinical relapse there has been considerable interest in ADAMTS13 monitoring and preemptive treatment. Indeed, preemptive treatment with rituximab has shown significant promise and is now included in the 2020 International Society on Thrombosis and Haemostasis (ISTH) treatment guidelines. Evaluation of long-term outcomes of ADAMTS13 based preemptive treatment have generally relied on limited numbers of historical controls which did not incorporate matching for known risk factors for relapse such as race, number of prior episodes, and immunosuppression. Our study aims to leverage the data in the United States Thrombotic Microangiopathy (USTMA) iTTP registry to compare the clinical relapse-free survival (RFS) intervals between iTTP patients treated preemptively based on ADAMTS13 level and those treated only for clinical relapse base on clinical and laboratory manifestations of iTTP. Methods: We carried out a retrospective study utilizing the multi-center cohort of patients with iTTP from the USTMA Consortium (spanning 1985-2019 and containing 780 participant records). We selected for patients with relapsing disease treated either preemptively based on ADAMTS13 level or for clinical relapse. Each preemptively treated episode was matched to up to five clinically relapsed episodes using covariate balancing propensity score nearest-neighbor matching by age, gender, race, prior relapse status, acute treatment, treatment center, and calendar year, with exact matching required for treatment center and prior relapse status. Time from prior episode to relapse was compared between preemptively treated episodes and matched controls using a Cox proportional hazards model weighted by the matching weights, including subclasses as a cluster, and using cluster-robust standard errors. Results: We identified 1068 episodes of iTTP. Of these. Thirteen participants accounting for a total of seventeen preemptive treatment episodes were included in the data set however, we included only the thirteen first uses of preemptive treatment to avoid selection bias. These were matched with 59 episodes treated for clinical relapse. Over 70% of the included participants in both groups were identified as black/African American. Distribution of immunosuppressive medications used in clinically relapsed cases were not significantly different than those used in preemptive treatment, and corticosteroids were the most frequently used. Demographic and treatment data before and after matching are included in Table 1. There was no significant difference in RFS between the groups, hazard ratio 0.63 (95% confidence interval 0.26-1.54), p=0.31. Conclusion: To our knowledge this is the first study to use matching controls to obtain a causal estimate of the effect of ADAMTS13 monitoring based preemptive treatment on RFS in iTTP. In contrast to previous work, we did not observe a significant increase in RFS in the preemptively treated group. It is possible that the limited number of preemptively treated episodes herein did not provide sufficient power to detect a difference. However, given the significant effect size that has been proposed, based on prior work, we suspect other factors may have also influenced this finding. Previous analysis of the USTMA iTTP registry has shown a higher incidence of relapse in African American participants. While the precise reason for this finding is not yet clear, it is worth considering that there may also be differential response to preemptive treatment. Our study highlights the importance of continued efforts to determine the generalizability and efficacy of ADAMTS13 monitoring based preemptive treatment in iTTP. Figure 1 Figure 1. Disclosures Gangaraju: Alexion: Consultancy; Sanofi Genzyme: Consultancy. Masias: Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. Parnes: Sigilon: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; I-mAb: Consultancy; Sunovion: Consultancy; Genentech/Hoffman LaRoche: Research Funding; UniQure: Membership on an entity's Board of Directors or advisory committees; Aspa: Consultancy. Mazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. OffLabel Disclosure: Rituximab, an anti CD20 monoclonal antibody will be discussed in relation to treatment of thrombotic thrombocytopenic purpura.

Cost-effectiveness of preemptive skin treatment to prevent skin-toxicity caused by panitumumab in third-line therapy for KRAS wild type metastatic colorectal cancer in Japan

Background Clinical management of skin-toxicity associated with the use of anti-Epidermal Growth Factor Receptor (EGFR) antibodies to treat colorectal cancer maintains quality of life of patients with colorectal cancer. Results of clinical trials have recommended the efficacy of prophylactic treatment, but the cost-effectiveness is unclear. This study examined the cost-effectiveness of preventive skin care for skin-toxicity caused by panitumumab in third-line therapy for KRAS wild type metastatic colorectal cancer from the perspective of the Japanese healthcare payer. Methods The data source was J-STEPP trial, which compared preemptive skin treatment with reactive treatment in third-line panitumumab therapy for KRAS wild type metastatic colorectal cancer in Japan. The costs and effectiveness of preemptive treatment was compared with reactive treatment in a 3-year time horizon using a 4-state partitioned survival analysis. The health outcome was quality-adjusted life-years (QALYs). The costs were 2020 revisions to the drug prices. The robustness of the model was verified by one-way sensitivity analysis and a probabilistic sensitivity analysis (PSA). A 2% annual discount was applied to the expenses and QALYs. Willingness-to-pay (WTP) threshold of 5 million JPY was used. Results Preemptive treatment had incremental effects of 0.0029 QALYs, incremental costs of 5300 JPY (48.6 USD), and incremental cost-effectiveness ratios (ICER) of 1,843,395 JPY (16,912 USD) per QALY. The variability of preemptive and reactive treatment costs for skin-toxicity and the disutility of skin-toxicity had a large impact on ICER. From PSA, the cost-effectiveness rate of preemptive treatment was 75.0%. Conclusions The cost to effectiveness of preemptive treatment to prevent skin-toxicity caused by panitumumab in third-line therapy for KRAS wild type mCRC is not high.

Early escitalopram administration as a preemptive treatment strategy against spasticity after contusive spinal cord injury in rats

In the majority of spinal cord injury (SCI) patients, spasticity develops in the subacute phase and chronically persists with muscle hypertonia. Among various pathological conditions underlying spasticity, upregulated expression of 5-HT receptors (5-HTR) on the spinal motor neurons due to 5-HT denervation is considered one of crucial factors for hyperexcitability of the spinal circuit. As a 5-HT signal modulator, selective serotonin re-uptake inhibitors (SSRIs) are ordinarily prescribed for diseases associated with 5-HT in the CNS, and are known for their ability to increase 5-HT levels as well as to desensitize 5-HTR. Here, we hypothesized that early SSRI administration as a preemptive treatment strategy would effectively prevent the onset of spasticity. We used a rat model of contusive SCI and administered escitalopram during the first 4 weeks after injury, which is the period required for spasticity development in rodent models. We performed a swimming test to quantify spastic behaviors and conducted the Hoffman reflex test as well as histological analyses for 5-HT2AR and KCC2 expressions. Four weeks of escitalopram administration suppressed spastic behaviors during the swimming test and reduced the population of spasticity-strong rats. Moreover, the treatment resulted in decreased immunoreactivity of 5-HT2AR in the spinal motor neurons. Result of the H-reflex test and membrane expression of KCC2 were not significantly altered. In summary, early escitalopram administration could prevent the onset of spastic behaviors via regulation of 5-HT system after SCI, but could not modulate exaggerated spinal reflex. Our results suggest a novel application of SSRIs for preventative treatment of spasticity.

Comparison of prophylactic versus preemptive treatments in the management of cytomegalovirus infection in renal transplant recipients

To prevent acute or chronic rejection in renal transplant recipients, immunosuppressive treatments are applied. However, immunosuppressive treatments increase the risk of cytomegalovirus (CMV) infection. The aim of this study was to evaluate the differences in efficacy and cost of prophylactic and preemptive treatment strategies applied in respect of CMV infection to renal transplant recipients. Methods. Patients who underwent renal transplantation in our center between 2010 and 2015, were retrospectively analyzed. The patients were allocated in two groups as those who received prophylaxis or preemptive treatment. A record was made of the kidney function tests (KFT), CMV PCR copy numbers, the presence of CMV infection, antiviral treatments received, and the costs were calculated of the tests and treatments. The groups were compared in respect of CMV infection and costs. Results. A total of 71 patients with a median age of 38 years (range, 19-74 years) were included in the study. The prophylaxis group included 43 patients and the preemptive group included 28 patients. CMV infection was detected in 7 (16.3%) of the prophylaxis group and 2 (7.1%) patients of the preemptive group (p=0.467). The cost per month of the tests and treatment was lower in the preemptive group than in the prophylaxis group (p<0.001). Conclusion. No significant difference was determined between the prophylactic and preemptive treatment protocols in respect of the CMV infection in the intermediate-risk group renal transplantation recipients. Preemptive treatment was seen to be a more cost-effective method than prophylactic treatment in Turkey.