We conducted an adaptive design single‐center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra‐short‐term perioperative pangenotypic direct acting antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)‐nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R−). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N = 15) and the posttrial validation (Group 2B; N = 25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12‐week DAA therapy. For available donor samples (N = 27), median donor viral load was 1.37E + 06 IU/mL (genotype [GT]1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% [3/10]; Group 2A:13% [2/15]; Group 2B:4% [1/25]). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first‐line DAA therapy; and two after retreatment with second‐line DAA). At a median follow‐up of 8 months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4‐day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval [CI]: 1.8%‐20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R − transplants.

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To cite this article: Lloyd NS, Douketis JD, Moinuddin I, Lim W, Crowther MA. Anticoagulant prophylaxis to prevent asymptomatic deep vein thrombosis in hospitalized medical patients: a systematic review and meta-analysis. J Thromb Haemost 2008; 6: 405-14.Summary. Background: The effect of anticoagulant prophylaxis on the prevention of deep vein thrombosis (DVT) should include an investigation of both clinical and subclinical DVT. We conducted a systematic review to determine whether anticoagulant prophylaxis reduces the risk of asymptomatic DVT compared to no prophylaxis in at-risk hospitalized medical patients. Methods: MEDLINE, EMBASE, and the Cochrane Library were searched through March 2007 for randomized trials of anticoagulant prophylaxis for the prevention of asymptomatic DVT, assessed by venogram or ultrasound. We assessed four outcomes: all asymptomatic DVT, asymptomatic proximal DVT, major bleeding and mortality. Random effects meta-analyses were performed and results were expressed using relative risk (RR) and 95% confidence intervals (95% CIs). Results: Four trials including 5516 patients were eligible. Our pooled analysis demonstrated that compared to placebo, anticoagulant prophylaxis was associated with a significantly lower risk of any asymptomatic DVT (RR 0.51; 95% CI 0.39-0.67) and asymptomatic proximal DVT (RR 0.45; 95% CI 0.31-0.65). Anticoagulant prophylaxis was associated with a significantly increased risk of major bleeding compared to placebo (RR 2.00; 95% CI 1.05-3.79). There was no significant difference in the pooled estimate for all-cause mortality. Anticoagulant prophylaxis conferred an absolute risk reduction of any DVT and proximal DVT of 2.6% and 1.8%, respectively, and was associated with a 0.5% absolute risk increase in major bleeding. Conclusions: Anticoagulant prophylaxis is effective in preventing asymptomatic DVT in at-risk hospitalized medical patients but is associated with an increased bleeding risk. The therapeutic benefits of anticoagulant prophylaxis appear to outweigh the risks of bleeding.

Background. Circulating donor-derived cell-free DNA (cfDNA), a minimally invasive diagnostic tool for kidney transplant rejection, was validated using traditional histology. The molecular microscope diagnostic system (MMDx) tissue gene expression platform may provide increased precision to traditional histology. Methods. In this single-center prospective study of 208 biopsies (median = 5.8 mo) posttransplant, we report on the calibration of cfDNA with simultaneous biopsy assessments using MMDx and histology by area under the curve (AUC) analyses for optimal criterion, as well as for, previously published cfDNA cutoffs ≤ 0.21% to “rule-out” rejection and ≥1% to “rule-in” rejection. Results. There were significant discrepancies between histology and MMDx, with MMDx identifying more antibody-mediated rejection (65; 31%) than histology (43; 21%); the opposite was true for T cell–mediated rejection [TCMR; histology: 27 (13%) versus MMDx: 13 (6%)]. Most of the TCMR discrepancies were seen for histologic borderline/1A TCMR. AUC for cfDNA and prediction of rejection were slightly better with MMDx (AUC = 0.80; 95% CI: 0.74-0.86) versus histology (AUC = 0.75; 95% CI: 0.69-0.81). A cfDNA ≤ 0.21% had similar sensitivity (~91%) to “rule-out” rejection by histology and MMDx. Specificity was slightly higher with MMDx (92%) compared with histology (85%) to “rule-in” rejection using cfDNA criterion ≥1%. Strong positive quantitative correlations were observed between cfDNA scores and molecular acute kidney injury for both “rejection” and “nonrejection” biopsies. Conclusions. Molecular diagnostics using tissue gene expression and blood-based donor-derived cell-free DNA may add precision to some cases of traditional histology. The positive correlation of cfDNA with molecular acute kidney injury suggests a dose-dependent association with tissue injury irrespective of rejection characteristics.

Here we report a single-center cohort of 6 patients (4 kidney-only, and 2 simultaneous liver/kidney transplants) diagnosed with COVID-19 at a median of 1.9 years (range=0.2-9.3 years) post-transplant. Five (of 6) patients required inpatient admission, two patients (mortality=33%) died. Among those with mortality, an increased concentration of inflammatory biomarkers [interleukin-6 (IL6) and C-reactive protein] was noted with a lack of response to IL-6 blockade, remdesivir and/or convalescent plasma. None of the kidney-only transplants (4/6; 67%) had elevation in plasma donor-derived cell-free DNA above the previously published cut-off of 1% suggesting absence of significant allo-immune injury. Four (of 5) admitted patients had detectable SARS-CoV-2 (severe acute respiratory syndrome–coronavirus 2) in blood on samples obtained at/during hospitalization. Of the 4 discharged patients, two patients with undetectable virus on repeat nasopharyngeal swabs had seroconversion with positive SARS-CoV-2 IgG formation at 30-48 days post-infection. One patient had prolonged shedding of virus on nasopharyngeal swab at 28 days post-discharge despite lack of symptoms. In this preliminary report, we find that immunocompromised transplant patients had higher rates of RNAemia (67%) than reported in the general population (15%), seeming absence of allo-immune injury despite systemic inflammation and formation of IgG overtime after recovery from infection.

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Trials describing 4-to 12-week courses of direct-acting antiviral drugs (DAAs) to treat hepatitis C virus (HCV) transmission from infected donors to uninfected kidney transplant recipients (D+/R− transplants) may be limited in "real-world" application by costs and delayed access to DAAs. We previously reported HCV transmission of 13% among D+/R− transplants with 2-to 4-day pangenotypic sofosbuvir/velpatasvir (SOF/VEL) perioperative prophylaxis, where one patient with HCV transmission was a nonresponder to first-line full-course DAA. Here, we report new data with a 7day prophylaxis protocol (N = 50), as well as cumulative treatment and outcome data on all HCV D+/R− transplants (N = 102). Overall, nine patients (9/102; 9%; 95% CI: 5%-16%) developed HCV transmission, with a significant decline noted in the 7-day group (2/50; 4%; 95% CI: 0%-13%) compared with 2-to 4-day prophylaxis (7/52; 13%; 95% CI: 5%-25%). All patients with HCV transmission achieved sustained virologic response post full-course therapy (including one nonresponder from initial trial). A 1:1 matched analysis (N = 102) with contemporary HCV D−/R− transplants (controls) showed that although the pretransplant wait time was significantly shorter for D+/ R− compared with D−/R− (mean: 1.8 vs. 4.4 years; p < .001), there were no differences in infections, rejection, development of de novo donor-specific antibody, or transplant outcomes up to 6 months of transplant.

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