Recurrent Viremia Research Articles

222.8: Effect of recurrent CMV viremia on graft and patient survival in renal transplantation.

222.8: Effect of recurrent CMV viremia on graft and patient survival in renal transplantation.

Efficacy and safety of tenofovir alafenamide in patients with chronic hepatitis B exhibiting suboptimal response to entecavir.

Entecavir (ETV) is a potent and safe antiviral agent for patients with chronic hepatitis B (CHB); however, some patients may exhibit suboptimal response or resistance to ETV. Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with improved pharmacokinetics and reduced renal and bone toxicity compared with tenofovir disoproxil fumarate. To evaluate the efficacy and safety of switching from ETV to TAF in patients with CHB exhibiting suboptimal response to ETV. A total of 60 patients with CHB who had been treated with ETV for at least 12 mo and had persistent or recurrent viremia [Hepatitis B virus (HBV) DNA ≥ 20 IU/mL] or partial virologic response (HBV DNA < 20 IU/mL, but detectable) were enrolled in the study. The patients were randomly assigned to either continue ETV (0.5 mg) daily or switch to TAF (25 mg) daily for 48 wk. The primary endpoint was the proportion of patients who achieved a virologic response (HBV DNA level < 20 IU/mL) at week 48. Secondary endpoints included changes in serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and anti-HBe levels, and renal and bone safety parameters. At week 48, the proportion of patients who achieved a virologic response was significantly higher in the TAF group than in the ETV group (93.3% vs 66.7%, P = 0.012). The mean reduction in HBV DNA from baseline was also significantly greater in the TAF group than in the ETV group (-3.8 vs -2.4 Log10 IU/mL, P < 0.001). The rates of ALT normalization, HBeAg loss, HBeAg seroconversion, and HBsAg loss were not found to significantly differ between the two groups. None of the patients developed genotypic resistance to ETV or TAF. Both drugs were well tolerated, with no serious adverse events or discontinuations caused by adverse events. No significant changes were observed in the estimated glomerular filtration rate, serum creatinine level, or urine protein-to-creatinine ratio in either group. The TAF group had a significantly lower decrease in bone mineral density at the lumbar spine and hip than the ETV group (-0.8% vs -2.1%, P = 0.004; -0.6% vs -1.8%, P = 0.007, respectively). Switching from ETV to TAF is effective and safe for patients with CHB exhibiting a suboptimal response to ETV and may prevent further viral resistance and reduce renal and bone toxicity.

Interim analysis: Open-label extension study of leniolisib for patients with APDS

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P= .004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. gov identifier: NCT02859727.

Analysis of the Contribution of 6-mer Seed Toxicity to HIV-1-Induced Cytopathicity.

HIV-1 (HIV) infects CD4+ T cells, the gradual depletion of which can lead to AIDS in the absence of antiretroviral therapy (ART). Some cells, however, survive HIV infection and persist as part of the latently infected reservoir that causes recurrent viremia after ART cessation. Improved understanding of the mechanisms of HIV-mediated cell death could lead to a way to clear the latent reservoir. Death induced by survival gene elimination (DISE), an RNA interference (RNAi)-based mechanism, kills cells through short RNAs (sRNAs) with toxic 6-mer seeds (positions 2 to 7 of sRNA). These toxic seeds target the 3' untranslated region (UTR) of mRNAs, decreasing the expression of hundreds of genes critical for cell survival. In most cells under normal conditions, highly expressed cell-encoded nontoxic microRNAs (miRNAs) block access of toxic sRNAs to the RNA-induced silencing complex (RISC) that mediates RNAi, promoting cell survival. HIV has been shown to inhibit the biogenesis of host miRNAs in multiple ways. We now report that HIV infection of cells deficient in miRNA expression or function results in enhanced RISC loading of an HIV-encoded miRNA HIV-miR-TAR-3p, which can kill cells by DISE through a noncanonical (positions 3 to 8) 6-mer seed. In addition, cellular RISC-bound sRNAs shift to lower seed viability. This also occurs after latent HIV provirus reactivation in J-Lat cells, suggesting independence of permissiveness of cells to viral infection. More precise targeting of the balance between protective and cytotoxic sRNAs could provide new avenues to explore novel cell death mechanisms that could be used to kill latent HIV. IMPORTANCE Several mechanisms by which initial HIV infection is cytotoxic to infected cells have been reported and involve various forms of cell death. Characterizing the mechanisms underlying the long-term survival of certain T cells that become persistent provirus reservoirs is critical to developing a cure. We recently discovered death induced by survival gene elimination (DISE), an RNAi-based mechanism of cell death whereby toxic short RNAs (sRNAs) containing 6-mer seed sequences (exerting 6-mer seed toxicity) targeting essential survival genes are loaded into RNA-induced silencing complex (RISC) complexes, resulting in inescapable cell death. We now report that HIV infection in cells with low miRNA expression causes a shift of mostly cellular RISC-bound sRNAs to more toxic seeds. This could prime cells to DISE and is further enhanced by the viral microRNA (miRNA) HIV-miR-TAR-3p, which carries a toxic noncanonical 6-mer seed. Our data provide multiple new avenues to explore novel cell death mechanisms that could be used to kill latent HIV.

Usefulness of dried blood spot samples for monitoring hepatitis C treatment outcome and reinfection among people who inject drugs in a test-and-treat program.

Dried blood spots (DBS) are a reliable tool to diagnose viremic hepatitis C virus (HCV) infection. We evaluated the clinical performance of a DBS-based molecular assay for the assessment of cure and reinfection after on-site treatment at a harm reduction center (HRC). Genotyping from DBS samples was also assessed to discriminate reinfection from treatment failure. People who inject drugs (PWID) from an ongoing test-and-treat pilot at the largest HRC in Barcelona were included in the study. HCV-RNA detection from DBS collected after treatment (with follow-up at 12, 36, and 60 weeks) was compared with a molecular point-of-care test using finger-stick blood (GeneXpert). Baseline and follow-up DBS samples were genotyped by NS5B sequencing or commercial real-time PCR. Among treated patients, 193 follow-up DBS samples were tested. The DBS-based assay showed 100% specificity (129/129), and sensitivity ranged from 84.4% to 96.1% according to different viral load cut-offs (from detectable to 3000 IU/mL). Sensitivity as test of cure (follow-up 12) ranged from 85.1% to 97.4%. Among the 64 patients with recurrent viremia, 10.9% had low viral loads (≤1000 IU/mL); HCV genotyping allowed us to classify 73.5% of viremic cases either as reinfection or as treatment failure. DBS samples are useful to assess cure and differentiate reinfection from relapse after HCV antiviral treatment in the real world, facilitating decentralization of treatment and posttreatment follow-up in PWID. However, a fraction of patients presented with low viral loads, limiting viremia detection and genotyping in DBS and, therefore, repeat testing is recommended.

Recurrent Cytomegalovirus Infection Controlled by the Introduction of Everolimus in a Simultaneous Pancreas-Kidney Transplantation Recipient: A Case Report

In simultaneous pancreas-kidney transplantation (SPK) recipients, cytomegalovirus (CMV) infection is a major complication that has been associated with the use of tacrolimus (TAC)-based immunosuppression. As one of the immunosuppressive drug options, the use of mammalian target of rapamycin inhibitors (mTORi) results in reduced rates of CMV infection in the field of solid organ transplantation. However, little is known about mTORi usage in pancreas transplantation. We report a case of recurrent CMV infection that was controlled by the introduction of mTORi (everolimus) in addition to a TAC-based immunosuppression regimen in SPK. A 52-year-old man underwent SPK. Graft duodenal perforation occurred on the 13th day of surgery, and graft duodenal resection was performed after long-term abscess drainage treatment. After graft duodenal resection, he was diagnosed with CMV viremia, and valganciclovir was started. However, because of recurrent febrile neutropenia caused by cytopenia as a side effect of valganciclovir, there was a repeated need for granulocyte-colony stimulating factor treatment. Immunosuppressive drug taper adjustment was attempted to control recurrent CMV viremia, and everolimus was introduced with the aim of reducing the dose of TAC and mycophenolate mofetil. This resulted in a continuously negative CMV antigenemia test and a stable general condition. Understanding the characteristics of various immunosuppressive agents and appropriately controlling and managing infectious diseases is crucial for the good postoperative management of patients with SPK.

Recurrent parvovirus B19 viremia resulting in two episodes of hemophagocytic lymphohistiocytosis

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition with uncontrolled activation of lymphocytes and macrophages. Besides a primary (genetic) form, HLH can also be triggered by malignant, autoimmune and infectious diseases. HLH recurrences are rarely described, usually only in primary HLH. Parvovirus B19 (PVB19) Infection is one of the rare and rather benign causes of HLH. Since the infection usually results in long-lasting immunity, recurrent viremia is very uncommon.Case presentationWe report an unusual case of a young female with recurrent PVB19 infection that led to repeated episodes of HLH. The first episode occurred at the age of 25 years with a three-week history of high fever and nonspecific accompanying symptoms. The diagnosis of HLH was confirmed by HLH-2004 criteria and HScore, PVB19 viremia was detected as underlying cause. Following guideline-based therapy, the patient was symptom-free for one year, before similar symptoms recurred in a milder form. Again, PVB19 was detected and HLH was diagnosed according to HScore. After successful treatment and a nine-month symptom-free interval, a third phase of hyperinflammation with low PVB19 viremia occurred; this time, treatment with a corticosteroid and intravenous immunoglobulin was initiated before the presence of clear diagnostic criteria for HLH. No further events occurred in the following three years.ConclusionsIn the case of our patient, the recurrent viremia triggered three episodes of hyperinflammation, two of which were clearly diagnosed as HLH. To our knowledge, this is the first published case of recurrent HLH due to PVB19 infection. Therefore, the case gives new insights in triggering mechanisms for HLH.

Recurrent CMV Viremia Portends Poor Prognosis and Results in Significant Resource Utilization in Patients with Poor Graft Function Post Allogeneic Stem Cell Transplantation

IntroductionPoor Graft Function (PGF) characterized by 2 or more lineage cytopenias in the setting of complete donor chimerism is a recognized complication of allogeneic stem cell transplantation (alloSCT). Recurrent CMV viremia jeopardizes blood count recovery in PGF through direct effect of the virus on bone marrow function as well as myelosuppression/organ toxicity due to widely available antivirals such as val/ganciclovir or foscarnet.MethodsTo assess the clinical effect and resource utilization of recurrent CMV viremia on patients with PGF we performed a retrospective analysis of alloSCT recipients at our Centre from 2018-2019. Patients were classified as having PGF based on the following parameters: 1) Donor myeloid chimerism ≥95% at last assessment, 2) 2 or more lineage cytopenias defined by Hb ≤85g/L, Neutrophils ≤1.0x10 9/L, Platelets ≤60x10 9/L, 3) cytopenias present for 10 days after D30. CMV viral loads were monitored by q PCR twice weekly with reactivation defined as the first reading quantifiable above the threshold of detection of the assay. Recurrent CMV reactivation was defined as detectable CMV after an interval of 4weeks without detectable virus, with patients who reactivated within 4 weeks of an undetectable viral load defined as prolonged persisting infection. Patients who died before D60 or who relapsed within the 1 st 100 days or those who had a prior alloSCT were excluded. Baseline factors in the CMV seropositive PGF group were evaluated by Chi Squared and Kruskall-Wallis test for categorical and continuous variables respectively to establish any associations with recurrent or persisting CMV. Survival analysis of PGF patients was performed by the Kaplan Meier method with patients stratified by the following: Recurrent CMV/Prolonged persisting infection (RP-CMV), Single CMV reactivation (S-CMV), No CMV reactivations (N-CMV) and CMV sero-negativity (S-NCMV). A descriptive analysis of the number of hospital admissions in addition to the initial alloSCT admission (extra admissions) and total hospital days was also performed.ResultsThere were 155 eligible patients of which 38 (24%) fulfilled criteria for PGF. The median follow-up of the cohort was 26 months (95%CI:23.1-28). The median overall survival (OS) of the cohort was not reached with an estimated 2 year OS of 73%. The 2 year OS of PGF patients was 59% compared to 78% in the non PGF group. There were no significant baseline associations found with RP-CMV (Table 1). Figure 1 demonstrates the survival of patients by nature of CMV reactivation. The 2 year OS by CMV reactivation was as follows: RP-CMV 25%, S-CMV 68%, N-CMV 70%, SN-CMV 87%.On univariate analysis, RP-CMV was significantly associated with mortality [HR 5.41; 95%CI 1.80-16.28; P=0.003]. This association remained significant when including Age and grade III-IV GVHD in multivariate analysis: RPCMV [HR 7.57; 95%CI 2.20-25.9;P=0.0013=], Age [HR 1.03; 95% CI 0.99-1.08; P=0.16] and GVHD [HR 2.91; 95%CI 0.87-9.75; P=0.08]. RP-CMV was not a risk factor for mortality within the NPGF population [HR 0.75; 95%CI 0.29-01.97; P=0.56]. Those with RP-CMV experienced an increase in their CMV viral load within a median of 4 days range (2-86) after achievement of an undetectable result. Those with PGF and RP-CMV had an average of 1.4 extra admissions with an average length of stay of 80 days, those with S-CMV reactivation had an average of 1.6 extra admissions with an average length of stay of 35 days, and those with N-CMV had an average of 1 extra admission with an average length of stay of 17 days. Those with SN-CMV had an average of 1 extra admission with an average length of stay of 23 days. CMV reactivation and CMV therapy contributed to 13/17 (76%) total readmissions for those with RP-CMV compared to 5/13 (38%) readmissions for those with S-CMV.ConclusionPatients with PGF and RP-CMV are at high risk of mortality as well as more lengthy hospital admissions of which CMV reactivation and CMV therapy is a potential contributor. Targeted use of novel therapies to prevent CMV reactivation in patients with PGF may improve both bone marrow function and survival leading to less resource utilization. [Display omitted] DisclosuresChee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Koldej: CRISPR Therapeutics: Research Funding. Ritchie: BMS: Research Funding; Takeda: Research Funding; CRISPR Therapeutics: Research Funding; Amgen Inc: Honoraria, Research Funding; CSL: Honoraria; Novartis: Honoraria.

Letermovir prophylaxis and cytomegalovirus reactivation in adult allogeneic hematopoietic cell transplant recipients with graft versus host disease.

7004 Background: Cytomegalovirus (CMV) is the most common clinically significant infection after allogeneic hematopoietic-cell transplantation (allo-HCT) and is associated with increased mortality. The risk for CMV reactivation increases with HLA mismatch, high dose corticosteroids, and graft versus host disease (GVHD). GVHD contributes to significant morbidity and mortality and is treated with immunosuppressive therapies that further increase CMV infection risk. In a phase III trial, letermovir prophylaxis had a lower incidence of CMV infection post-allo-HCT in patients at high risk of CMV reactivation when compared to placebo when given up to day +100. There is a lack of data concerning the effectiveness of letermovir in patients who develop GVHD and may continue letermovir past day +100. Methods: This was a single-center, retrospective study conducted at The Ohio State University. Demographics and transplant details were collected from medical records. The primary outcome was incidence of clinically significant CMV infection (CS-CMVi) within 200 days of allo-HCT. Secondary outcomes included incidence of CMV viremia, duration of letermovir therapy, mortality, and risk factors for CS-CMVi. Early death without CMV was treated as a competing risk for CS-CMVi, while relapse was a competing risk for non-relapse mortality (NRM). Proportional subdistribution or Cox hazards models were used to evaluate the association between use of letermovir and risk of CS-CMVi, NRM, or overall survival (OS) adjusting for potential confounding factors, where use of letermovir and GVHD were treated as time-dependent variables. Results: A total of 262 CMV-seropositive patients who received an allo-HCT between June 1, 2016 and June 30, 2020 were included. Of these, 119 patients received letermovir prophylaxis. A total of 111 patients received treatment for CS-CMVi, which included 82 of 143 (57%) who did not receive letermovir compared to 29 of 119 (24%) who received letermovir. Incidence of CMV viremia was significantly reduced with the use of letermovir in all patients (HR 0.21, 95% CI 0.12–0.34, p &lt; 0.001) and among patients with acute GVHD grade &gt;2 within 200 days post-allo-HCT (HR 0.12, 95% CI 0.05–0.32, p &lt; 0.001), adjusting for age, gender, GVHD prophylaxis and use of ATG or T-cell depleted graft. The median duration of letermovir therapy was 97 days. Nine patients were continued on letermovir indefinitely for recurrent CMV viremia. Patients who received letermovir had decreased NRM (HR 0.41, 95% CI 0.18-0.96, p = 0.04) and improved OS (HR 0.46, 95% CI 0.23-0.95, p = 0.04). Conclusions: Letermovir prophylaxis significantly decreased CS-CMVi and improved NRM and OS in this real-world analysis. In addition, patients with acute GVHD had significantly less CMV viremia, suggesting potential benefit in continuing letermovir prophylaxis in this patient population.

The Longest Persistence of Viable SARS-CoV-2 With Recurrence of Viremia and Relapsing Symptomatic COVID-19 in an Immunocompromised Patient-A Case Study.

BackgroundImmunocompromised patients show prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal swabs. We report a case of prolonged persistence of viable SARS-CoV-2 associated with clinical relapses of coronavirus disease 2019 (COVID-19) in a patient with mantle cell lymphoma who underwent treatment with rituximab, bendamustine, cytarabine with consequent lymphopenia and hypogammaglobulinemia.MethodsNasopharyngeal swabs and blood samples were tested for SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR). On 5 positive nasopharyngeal swabs, we performed viral culture and next-generation sequencing. We analyzed the patient’s adaptive and innate immunity to characterize T- and NK-cell subsets.ResultsSARS-CoV-2 RT-PCR on nasopharyngeal swabs samples remained positive for 268 days. All 5 performed viral cultures were positive, and genomic analysis confirmed a persistent infection with the same strain. Viremia resulted positive in 3 out of 4 COVID-19 clinical relapses and cleared each time after remdesivir treatment. The T- and NK-cell dynamic was different in aviremic and viremic samples, and no SARS-CoV-2-specific antibodies were detected throughout the disease course.ConclusionsIn our patient, SARS-CoV-2 persisted with proven infectivity for >8 months. Viremia was associated with COVID-19 relapses, and remdesivir treatment was effective in viremia clearance and symptom remission, although it was unable to clear the virus from the upper respiratory airways. During the viremic phase, we observed a low frequency of terminal effector CD8+ T lymphocytes in peripheral blood; these are probably recruited in inflammatory tissue for viral eradication. In addition, we found a high level of NK-cell repertoire perturbation with relevant involvement during SARS-CoV-2 viremia.

Unexpected Cytomegalovirus (CMV) Replication Kinetics in CMV Donor-Seropositive, Recipient-Seronegative Liver Transplant Recipients Receiving Preemptive Antiviral Therapy.

Detailed cytomegalovirus (CMV) kinetics in donor CMV-seropositive, recipient CMV-seronegative (D+/R-) transplant recipients receiving preemptive therapy (PET) have not been fully defined. The study population consisted of the PET arm of a randomized CMV prevention trial in D+/R- liver transplant recipients. CMV DNA polymerase chain reaction (PCR) assays were performed weekly for 100 days using a sensitive assay. Viral load and clinical parameters were compared for patients with or without high-level increase (defined as higher than the group median log10 increase in viral load from baseline after PET initiation). Among 79 patients, 93.6% (74/79) developed an increase from baseline viral loads of median 120 IU/mL to 3350 IU/mL; 25.7% (19/74) of the patients had peak levels >10 000 IU/mL. None of the patients with rise in viral load underwent testing for CMV resistance, and viremia resolved with PET with valganciclovir. Patients with high-level increase in viral load had a significantly lower rate of recurrent viremia than those without such increase (16/40 [40%] vs 28/39 [71.8%], respectively; P = .004). A majority of D+/R- recipients had a marked increase in viral load after initiation of PET before resolution of viremia. This phenomenon is associated with lower rates of subsequent recurrent viremia and does not necessarily imply antiviral resistance.

Outcome of Chinese patients with hepatitis B at 96 weeks after functional cure with IFN versus combination regimens.

Nucleotides with add-on interferon treatment (NUC-IFN) provide significantly higher rates of hepatitis B surface antigen (HBsAg) loss in patients with chronic hepatitis B (CHB). This study aimed to investigate the sustainability of HBsAg loss and the prevention of clinical relapse. Patients with CHB who achieved HBsAg loss and HBV DNA levels <20IU/ml after IFN or NUC-IFN therapy were enrolled and followed up for 96weeks. The primary outcome was HBsAg negativity without viremia at week 96. Secondary outcomes included virological or clinical relapse and predictors of relapse. 420 patients were included in intention-to-treat analysis with 290 and 130 in the IFN and NUC-IFN groups respectively. At week 96, the intention-to-treat analysis revealed similar outcomes between groups, including HBsAg seroreversion (24.83% vs. 23.08%, P=.70), viremia (16.90% vs 13.08%, P=.32) and clinical relapse (11.38% vs 10.00%, P=.68); the per-protocol analyses also showed HBsAg seroreversion, viremia and clinical relapse in IFN group (15.50%, 6.59% and 0.39%) did not differ from those in NUC-IFN group (15.25%, 4.24% and 0.85%, P>.05). These outcomes were similar between patients who received entecavir and those who received telbivudine/lamivudine/adefovir before the combination therapy. In NUC-IFN-treated patients, fibrosis regression was observed at week 96. Baseline HBsAb negativity was independent predictors of HBsAg sero-reversion and recurrence of viremia in IFN treated group. NUC-IFN and IFN therapies are equally effective in achieving sustained functional cure and fibrosis regression. (ClinicalTrials.gov, Number NCT02336399).

582. Safety and Efficacy of High-Dose Ganciclovir versus Standard Dosing for Cytomegalovirus Viremia in Solid Organ Transplant (SOT) Recipients

BackgroundStandard dose ganciclovir (SD-GCV) for treatment of CMV infection/disease is 5 mg/kg every 12 hours, although higher doses (7.5–10 mg/kg every 12 hours) may be considered for resistant CMV. Literature on safety/efficacy of high dose GCV (HD-GCV) is limited. We sought to evaluate safety and clinical outcomes of SD-GCV vs HD-GCV strategies.MethodsRetrospective single center study of adult SOT recipients with CMV viremia from 1/1/2017-1/31/2019 who received IV GCV therapy. Primary objective was to compare incidence of cytopenias between SD-GCV and HD-GCV. Secondary outcomes compared CMV viremia clearance, incidence of CMV disease and recurrent viremia within 30 days, granulocyte colony stimulating factor (G-CSF) use, and antiviral resistance testing rates.ResultsWe evaluated 121 patients: 74 received SD-GCV, 47 received HD-GCV. Baseline characteristics were similar between groups. Most patients received a liver transplant (46% SD vs 36% HD) and had D+/R- CMV serostatus (55.4% SD vs 68% HD). Induction immunosuppression occurred in 75%, mostly with anti-thymocyte globulin. Median baseline CMV viral loads were similar (4620 IU/mL SD vs 7770 IU/mL HD, p=0.25).Incidence of cytopenias was similar between groups: leukopenia (43% SD vs 43% HD, p=0.96), neutropenia (15% SD vs 13% HD, p= 0.75), thrombocytopenia (24% SD vs 31% HD, p=0.62). HD-GCV did not significantly impact CMV clearance (HR: 0.79 [95% CI 0.52–1.21], p=0.27). There was no difference in incidence of CMV disease (35% SD vs 38% HD, p=0.72) or incidence of recurrent CMV viremia (15% SD vs 28% HD, p=0.098).G-CSF requirement was not different (23.7% SD vs 14.3% HD, p=0.295), however, patients on HD-GCV received more doses of G-CSF (median 2 SD vs 5 HD, p=0.001). More patients in HD-GCV group were tested for antiviral resistance: 15 (21%) SD vs 20 (43%) HD, p=0.01. Of these, there was no difference in rate of resistance detection (7/15 (47%) SD vs 11/20 (55%) HD, p=0.95).ConclusionTherapy with HD-GCV did not demonstrate increased incidence of cytopenias compared to SD-GCV, nor did we observe improved time to CMV clearance or incidence of CMV disease between groups. Opportunities exist for improving stewardship of antiviral resistance testing and use of G-CSF when considering HD-GCV therapy.Disclosures All Authors: No reported disclosures

S2693 Outcome of Hepatitis C Virus-Positive Liver Transplantation for Telomere-Mediated HPS-Noncirrhotic Portal Hypertension After Bone Marrow Transplantation: A Case Report

INTRODUCTION: Short telomere syndromes are disorders caused by germline mutations in genes regulating telomere maintenance. Their phenotypes and severity vary and depend on the extent of telomere shortening. Dyskeratosis congenita (DC) is a prototypic short telomere syndrome, characterized by bone marrow failure, liver disease (noncirrhotic portal hypertension, cryptogenic cirrhosis), pulmonary fibrosis and an increased risk of malignancy. With contemporary hematopoietic stem cell transplantation (HSCT) regimens, non-cirrhotic portal hypertension with hepatopulmonary syndrome (HPS) is the most common morbidity. We describe successful HCV-positive liver transplantation (LT) for telomere-mediated noncirrhotic portal hypertension with HPS after HSCT. CASE DESCRIPTION/METHODS: A 27-year-old female with DC complicated by noncirrhotic portal hypertension and HPS underwent LT at age 25, from a 23-year-old, HCV-positive, female donor. The recipient was diagnosed with bone marrow failure and DC at age 17. At that time, telomere length was below the 1st age-adjusted percentile, but she had no identifiable mutation. She underwent a non-myeloablative HSCT at age 19. Three years later, she presented with progressive dyspnea and was found to have stigmata of portal hypertension and intrapulmonary shunt. A trans-jugular liver biopsy confirmed the absence of significant fibrosis with a hepatic venous pressure gradient of 10 mmHg. Her dyspnea continued to progress with minimal evidence of parenchymal pulmonary fibrosis but worsening HPS. She was on 10 L oxygen prior to LT with room air PO2 55 mmHg, qualifying for UNOS upgrade to MELD 29. Liver explant pathology revealed focal parenchymal nodularity and absence of significant fibrosis. She had a prolonged recovery due to respiratory failure and malnutrition, which she recovered from and completely weaned off oxygen four months post-LT. She was successfully treated for HCV post-LT. She had recurrent low-level CMV viremia and presumed mild graft rejection episode. Sixteen months post-LT, she continues to be on room air with stable lung and liver graft function. DISCUSSION: The natural history of short telomere syndromes is marked by progressive noncirrhotic portal hypertension with HPS, a frequent long-term complication after HSCT. We report a successful LT and reversal of hypoxemia after an HCV-positive LT in a patient with DC. Sequential transplant may be feasible option for post-HSCT patients who develop end-stage liver disease.

Outcomes of Hepatitis C Virus Treatment in the New York City Jail Population: Successes and Challenges Facing Scale up of Care.

BackgroundThe population detained in the New York City (NYC) jail system bears a high burden of hepatitis C virus (HCV) infection. Challenges to scaling up treatment include short and unpredictable lengths of stay. We report on the clinical outcomes of direct-acting antiviral (DAA) treatment delivered by NYC Health + Hospitals/Correctional Health Services in NYC jails from 2014 to 2017.MethodsWe performed a retrospective observational cohort study of HCV patients with detectable HCV ribonucleic acid treated with DAA therapy while in NYC jails. Some patients initiated treatment in jail, whereas others initiated treatment in the community and were later incarcerated. Our primary outcome was sustained virologic response at 12 weeks (SVR12).ResultsThere were 269 patients included in our cohort, with 181 (67%) initiating treatment in jail and 88 (33%) continuing treatment started in the community. The SVR12 virologic outcome data were available for 195 (72%) individuals. Of these, 172 (88%) achieved SVR12. Patients who completed treatment in jail were more likely to achieve SVR12 relative to those who were released on treatment (adjusted risk ratio, 2.93; 95% confidence interval, 1.35–6.34). Of those who achieved SVR12, 114 (66%) had a subsequent viral load checked. We detected recurrent viremia in 18 (16%) of these individuals, which corresponded to 10.6 cases per 100 person-years of follow-up.ConclusionsHepatitis C virus treatment with DAA therapy is effective in a jail environment. Future work should address challenges related to discharging patients while they are on treatment, loss to follow-up, and a high incidence of probable reinfection.

First Reported Treatment Failure in a Recipient of a Hepatitis C Viremic Heart Transplant

Cardiac transplant centers are now successfully utilizing hepatitis C virus (HCV) donor hearts to increase the availability of organs now that a curative treatment is available with direct acting antivirals (DAA). We present the first described case of DAA treatment failure in a patient who received an HCV donor, nucleic acid testing (NAT) positive heart. A 65-year-old male with a mixed cardiomyopathy underwent orthotopic heart transplant with an HCV+/NAT+ heart. He seroconverted within seven days of transplant, noted by a peak HCV viral load of 7.65 log IU/mL and genotype of 1a without resistance markers. Planned initial treatment with glecaprevir/pibrentasvir (G/P) was denied by insurance. After approval for and treatment with ledipasvir/sofosbuvir (L/S) for 8 weeks, the patient's viral load was initially undetectable. However, he developed recurrent viremia 6 months after treatment completion with an HCV load of 7.40 log IU/mL with NS5A resistance due to a Y93H mutation. He was subsequently initiated on sofosbuvir/velpatasvir/voxilaprevir (S/V/V) with persistent undetectable viral loads to date at 4 months. This is the first documented case of DAA treatment failure in a recipient of HCV+/NAT+ transplanted heart treated with L/S. This treatment failure was likely secondary to insufficient treatment duration. The ION-3 study demonstrated noninferiority for an 8 week treatment duration compared to 12 weeks of L/S, but at the cost of a higher relapse rate in the 8 week arm (5% vs 1%) associated with viral load of >6.78 log IU/mL. The Y93H mutation is more likely to reduce treatment efficacy in L/S as noted by a pooled resistance analysis compared to G/P, which has a failure rate of <1%. In our case, resistance may have been prevented by 12 weeks of L/S or initial use of G/P for 8 weeks, as supported by the ENDURANCE-1 trial. In the new era of HCV transplantation, selection of DAA and duration of treatment are critical. Awareness of the resistance development data is needed when selecting HCV treatment regimens.

Quantitation of CMV Specific T-Cell Expansion Using T Cell Receptor Beta Locus Deep Sequencing to Identify Patients at Risk of Viral Complications

<h3>Background/Aim</h3> An effective T cell response is necessary for the control of cytomegalovirus (CMV) reactivation after allogeneic stem cell transplant (alloBMT) - CMV is associated with significant morbidity, especially in patients (pts) who require recurrent episodes of antiviral therapy & those who develop associated end organ dysfunction (CMV disease). We sought to determine whether deep sequencing of T cell receptor beta (TRB) loci could identify & quantitate T cell clonotypes with specificity for CMV epitopes in the early post-alloBMT period and assess association with virus related outcomes. <h3>Methods</h3> TRB deep sequencing was performed using LymphoTrack TRB (Invivoscribe) on stored DNA samples, extracted from CD3+ selected peripheral blood samples taken at Day+30 & Day+60 from 65 consecutive pts receiving alloBMT at our institution, who were donor (D) &/or recipient (R) CMV seropositive. Sequence assembly, annotation & error correction was performed by MiXCR/VDJtools. Epitope specificity was assessed using a curated database of T cell clonotype/epitope specificity (VDJdb). Statistical analysis was performed using the Kaplan-Meier method for time to event endpoints, Fisher's exact test for discrete variables & the Mann Whitney U test for continuous variables. <h3>Results</h3> CMV specific T cells were identifiable in 97% samples at D+30 & 100% samples at D+60 - the proportion of the T cell repertoire comprising CMV specific T cells (CMV-Trep%) was median (IQR) 0.15% (0.04-0.55%) & 0.12% (0.05-0.66%) respectively. Antecedent viremia was associated with a higher CMV-Trep% at both time points (D+30: 0.45% vs, 0.095%, p=0.01; D+60: 0.20% vs. 0.07%, p=0.02), as was D+R+ serostatus at D+60 (0.28%, p=0.003). Pts who developed detectible viremia between the two sample timepoints had a median 2.1-fold increase in CMV-Trep% (vs. 0.1-fold decrease for those without viremia, p=0.03). 45% of pts had at least 1 episode of anti-CMV therapy, 52% of whom required >1 episodes of treatment. CMV disease developed in 11% of pts. Time to first antiviral treatment was associated with ATG (HR 2.5, p<0.01), unrelated donor (HR 2.0, p=0.04) & non D+R- serostatus (HR 6.0, p<0.01), and was not predicted by CMV-Trep% at either timepoint. Conversely, following initial reactivation requiring antiviral therapy, pts with CMV-Trep >0.1% at D+60 were significantly less likely to require additional episodes of antiviral therapy (HR 0.32, p=0.05) or develop CMV related organ dysfunction (HR 0.15, p=0.02). No clinical factor was associated with these outcomes. <h3>Conclusion</h3> The degree of post-reactivation expansion of CMV specific T cells can be quantified using TRB deep sequencing. Identification of pts who fail to mount a T cell response to initial reactivation may be predictive of those at high risk for recurrent viremia & CMV disease, in whom secondary prophylactic interventions (e.g. antiviral or cellular therapy) could be used.

Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients.

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+06IU/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 8months 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.

Genomic Characterization of a Pediatric Cohort with Non-Malignant Lymphoproliferative Disorders

Introduction: Pediatric non-malignant lymphoproliferative disorders (LPDs) are a clinically and genetically heterogeneous. While transient lymphadenopathy is extremely common and rarely dangerous, long-standing immune dysregulation and lymphoproliferation in children may be life-threatening. Data to guide evaluation and treatment of children with benign LPD are lacking. The primary objective of this study was to define the genomic spectrum and clinical characteristics of a cohort of children with nonmalignant LPD. Identification of the underlying pathogenic mechanisms may facilitate timely interventions and potentially guide optimal therapeutic strategies. Method s: Patients at Texas Children's Hospital and collaborating referral centers who met criteria for non-malignant LPD were offered participation in this study, approved by the Baylor College of Medicine Institutional Review Board. LPD was defined as persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant EBV infection. Chronic or significant EBV infection was defined as recurrent or persistent EBV viremia more than 3 months, invasive EBV disease, or EBV PCR copies &amp;gt;100,000. All subjects and/or family members provided written informed consent to have their clinical and genetic information published. Genetic testing was performed clinically or through research-based whole-exome sequencing (WES). Results : Fifty-one subjects from 47 different families with non-malignant LPD were identified. Median age at disease presentation was 3.3 years (range 3.9 weeks - 21 years) with nearly equal proportions of males (n = 26) and females (n = 25). Almost half of subjects were Hispanic (49%), and 29% were non-Hispanic white. Fifteen subjects (29%) met HLH-2004 diagnostic criteria for HLH. Twenty-one patients had EBV-associated lymphoproliferative disorders (EBV-LPD) and 6 of the 51 ultimately developed malignancy. Clinical genetic testing was performed in 29 patients, and research-based WES was performed in 44 patients. Potential disease-causing genetic defects were identified in 62% of families. Of these pathogenic variants, targeted therapies may be effective for treatment in at least 10 of the conditions (17 subjects, 33%). Furthermore, genetic results supported potential for curative HSCT in 35% of the patients. Mechanistically, all of the LPD-associated genes could be placed into 1 of 3 categories: 1) defective control of lymphocyte activity; 2) impaired lymphocyte activation, cytoskeletal organization, and apoptosis; and 3) dysregulated inflammation. Ten-year survival for the entire cohort was 72.4% with a median 5.6 years of follow-up (range 0.10 - 26.6). Patients without evidence of a genetic explanation had a lower ten-year survival compared to those patients for whom a genetic explanation was identified (48% versus 82%, respectively, p=0.03). When both EBV-LPD and genetic explanation were considered, the ten-year survival estimate for those with EBV-associated disease and no genetic explanation was significantly worse than those with EBV-associated disease and a genetic explanation (17% vs. 90%; p =0.002). Patients without EBV-associated disease were at lower risk of death than those with EBV-LPD. Evaluating outcomes associated with maximum treatment received, ten-year survival was lowest (25% survival) among those who underwent HSCT. Conclusion s: Pediatric non-malignant LPD represents a group of conditions with high risk of death. WES identified actionable mutations in the majority of LPD cases in this cohort. Early identification of these mutations can guide therapy by confirming diagnosis, revealing molecular targets and/or supporting definitive therapy with stem cell transplant. Disclosures Forbes: Takeda: Consultancy. Jolles:CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; LFB: Consultancy, Honoraria, Research Funding, Speakers Bureau; UCB Pharma: Consultancy, Other: Drug Safety Committee; Shire/Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharming: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Heslop:Marker Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Allovir: Equity Ownership; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cell Medica: Research Funding. Rouce:Novartis: Consultancy, Honoraria; Tessa Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria.

Genetic Polymorphisms within Interferon-λ Region and Interferon-λ3 in the Human Pathophysiology: Their Contribution to Outcome, Treatment, and Prevention of Infections with Hepatotropic Viruses.

Genetic polymorphisms within the interferon λ (IFN-λ) chromosomal region, mainly rs12979860 of IFN-λ4 gene (IFNL4), are known as associated with spontaneous hepatitis C virus (HCV) resolution and sustained viral response to therapy with pegylated interferon- α and ribavirin. Strong linkage disequilibrium of IFNL4 rs12979860 with IFNL4 rs368234815, which is casually associated with HCV spontaneous and therapeutical eradication, at least partially explains favorable HCV outcomes attributed to major homozygosity in rs12979860. Effects of IFN-based antiviral treatment are associated with pretreatment expression of the IFN-λ1 receptor, expression of hepatic IFN-stimulated genes, production of IFN- λ4, and preactivation of the JAK-STAT signaling. Nowadays direct-acting antivirals (DAAs) became a potent tool in the treatment of hepatitis C, but IFN-λs are still under investigation as potential antivirals and might be an option in HCV infection (DAA resistance, recurrent viremia, adverse effects). Patients with altered immunocompetence are especially prone to infections. In uremic subjects, polymorphisms within the IFN-λ chromosomal region associate with spontaneous HCV clearance, similarly like in the non-uremic population. Circulating IFN-λ3 shows a positive correlation with plasma titers of antibodies to surface antigen of hepatitis B virus (anti-HBs), which are crucial for protection against hepatitis B virus. More efficient anti-HBs production in the presence of higher IFN-λ3 levels might occur due to IFN-λ3-induced regulation of indoleamine 2,3-dioxygenase (IDO) expression. IFN-stimulated response element is a part of IDO gene promoter. It is worth further investigation whether IDO gene, circulating IDO, genetic polymorphisms within the IFN-λ region, and circulating IFN-λ3 act in concordance in immunological response to hepatotropic viruses.