...this risk is lower in patients with T-cell-repleted graft versus patients receiving T-cell-depleted transplant.2 During the posttransplant period, several prophylactic or preemptive antiviral ...treatments may be partially effective by inhibiting viral replication and thus stabilizing the viral load.3,4 However, antiviral drugs can also induce drug resistance and be responsible for organ toxicity.5 Because the transfer of donor memory T lymphocytes directed specifically against immunodominant viral antigens has been shown to control ongoing viral infections, we designed a French multicenter pilot trial (Clinicaltrials.gov: NCT01325636) with the aim of treating pediatric or adult recipients of allogeneic HSCT (regardless of the underlying disease).6-8 Inclusion criteria were as follow: (1) donor chimerism 10% or more at inclusion; (2) biological signs of infection with CMV with resistance or intolerance to conventional antiviral treatments, or CMV or ADV disease with documented organ damage; (3) graft versus host activity (<=II) controlled by corticoids (<1 mg/kg) at the time of inclusion; and (4) donor with positive CMV and/or ADV serology. Patient SAE Delay between SAE and specific T-cell infusion P1 Multivisceral failure due to disseminated CMV infectionDeath Day+7Day+31 P2 None NA P3 None NA P4 Sepsis Day+1 P5 Worsening respiratory symptoms 5 mo P6 Alveolar hemorrhage and death Day+3 P7 Gram-negative sepsis Day+12 P8 Pulmonary hypertension and intraalveolar hemorrhageDeath Day+36Day+96 P9 Multivisceral failureDeath Day+10Day+14 P10 Stage III GvHDDeath from ADV pneumonitis Day+5Day+97 P11 Intraalveolar hemorrhage, hematemesisDeath Day+14Day+25 P12 None NA P13 SepsisPneumopathy Day+23Day+48 P14 Respiratory distressDeath from PTLD Day+20Day+33 P15 Acute respiratory distress syndrome due to CMV and ADV and death Day+3 Table E3 Serious adverse event observed in treated patients GvHD, Graft versus host disease; NA, not applicable; P, patient; PTLD, posttransplant lymphoproliferative disease.
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...the cells were washed, and flow cytometric analysis was performed immediately thereafter on a FACS scanner (Becton Dickinson Biosciences, Franklin Lakes, NJ). ...Fig 2 shows the predicted ...concentration time course of rATG after 3 successive daily doses of 4 mg/kg administered over 12 hours.
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Objective Given the lack of data regarding the use of oseltamivir (Tamiflu) during pregnancy, we aimed to evaluate the placental transfer of oseltamivir phosphate and its active metabolite ...oseltamivir carboxylate, using the perfused placental cotyledon model. Study Design Cotyledons were coperfused with oseltamivir phosphate and oseltamivir carboxylate using the maximal concentrations described with a 75 mg, twice-daily oral dose. Main transfer parameters such as fetal transfer rate (FTR) and clearance index (CI) were assessed. Results Five placentas were coperfused with oseltamivir phosphate and oseltamivir carboxylate. The median FTR of oseltamivir phosphate was 8.5% (range, 5.0–11.6%) and the median CI was 0.3 (range, 0.2–0.6). Regarding oseltamivir carboxylate transplacental transfer, the median FTR was 6.6% (range, 3.9–9.7%), whereas the median CI was 0.2 (range, 0.2–0.5). Conclusion A transplacental transfer of oseltamivir phosphate and its metabolite oseltamivir carboxylate was detected and might have clinical relevance. Clinicians should be encouraged to report oseltamivir treatment outcomes during pregnancy.
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Objectives The use of taxanes (paclitaxel and docetaxel) in pregnant cancer patients is increasing. We aimed to compare their transplacental transfer using the gold standard human placental perfusion ...model, to guide drug selection. Study Design Term placentas were perfused with paclitaxel or docetaxel and 2 different albumin concentrations. Main transfer parameters such as fetal transfer rate (FTR), clearance index, and placental uptake of taxanes were assessed. Results Twelve placentas were perfused, 6 with paclitaxel and 6 with docetaxel. Mean FTR of paclitaxel decreased significantly from 5.67 ± 0.02% in low albumin conditions to 1.72 ± 0.09% in physiological albumin conditions. Similarly, mean clearance index decreased significantly from 0.22 ± 0.02 to 0.09 ± 0.01. Regarding docetaxel, mean FTR were similar in low albumin and physiological conditions (5.03 ± 0.60% and 4.04 ± 0.22%, respectively) while mean clearance index decreased significantly from 0.18 ± 0.02 to 0.13 ± 0.01. Taxanes accumulation in cotyledon was similar for docetaxel and paclitaxel: 4.54 ± 1.84% vs 3.31 ± 1.88%, respectively. Conclusion Transplacental transfer and placental accumulation of paclitaxel and docetaxel were low and similar, especially in physiological conditions of albumin. Further studies are warranted to optimize the selection of a taxane in pregnant cancer patients.
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Summary Background Strategies to prevent postnatal mother-to-child transmission of HIV-1 in Africa, including infant prophylaxis, have never been assessed past 6 months of breastfeeding, despite ...breastfeeding being recommended up to 12 months after birth. We aimed to compare the efficacy and safety of infant prophylaxis with the two drug regimens (lamivudine or lopinavir–ritonavir) to prevent postnatal HIV-1 transmission up to 50 weeks of breastfeeding. Methods We did a randomised controlled trial in four sites in Burkina Faso, South Africa, Uganda, and Zambia in children born to HIV-1-infected mothers not eligible for antiretroviral therapy (CD4 count >350 cells per μL). An independent researcher electronically generated a randomisation schedule; we then used sequentially numbered envelopes to randomly assign (1:1) HIV-1-uninfected breastfed infants aged 7 days to either lopinavir–ritonavir or lamivudine (paediatric liquid formulations, twice a day) up to 1 week after complete cessation of breastfeeding or at the final visit at week 50. We stratified the randomisation by country and used permuted blocks of four and six. We used a study label on drug bottles to mask participants, study physicians, and assessors to the treatment allocation. The primary outcome was infant HIV-1 infection between age 7 days and 50 weeks, diagnosed every 3 months with HIV-1 DNA PCR, in the modified intention-to-treat population (all who attended at least one follow-up visit). This trial is registered with ClinicalTrials.gov , number NCT00640263. Findings Between Nov 16, 2009, and May 7, 2012, we enrolled and randomised 1273 infants and analysed 1236; 615 assigned to lopinavir–ritonavir or 621 assigned to lamivudine. 17 HIV-1 infections were diagnosed in the study period (eight in the lopinavir–ritonavir group and nine in the lamivudine group), resulting in cumulative HIV-1 infection of 1·4% (95% CI 0·4–2·5) and 1·5% (0·7–2·5), respectively. Infection rates did not differ between the two drug regimens (hazard ratio HR of lopinavir–ritonavir versus lamivudine of 0·90, 95% CI 0·35–2·34; p=0·83). Clinical and biological severe adverse events did not differ between groups; 251 (51%) infants had a grade 3–4 event in the lopinavir–ritonavir group compared with 246 (50%) in the lamivudine group. Interpretation Infant HIV-1 prophylaxis with lopinavir–ritonavir was not superior to lamivudine and both drugs led to very low rates of HIV-1 postnatal transmission for up to 50 weeks of breastfeeding. Infant pre-exposure prophylaxis should be extended until the end of HIV-1 exposure and mothers should be informed about the persistent risk of transmission throughout breastfeeding. Funding INSERM/National Agency for Research on AIDS and Viral Hepatitis (including funds from the Total Foundation), European Developing Countries Clinical Trials Partnership, Research Council of Norway.
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