ABSTRACT
BACKGROUND: Novel treatments are needed for Staphylococcus aureus bacteremia, particularly for methicillin-resistant S. aureus (MRSA). Exebacase is a first-in-class antistaphylococcal lysin that is rapidly bactericidal and synergizes with antibiotics. METHODS: In Direct Lysis of Staph Aureus Resistant Pathogen Trial of Exebacase (DISRUPT), a superiority-design phase 3 study, patients with S. aureus bacteremia/endocarditis were randomly assigned to receive a single dose of intravenous exebacase or placebo in addition to standard-of-care antibiotics. The primary efficacy outcome was clinical response at day 14 in the MRSA population. RESULTS: A total of 259 patients were randomized before the study was stopped for futility based on the recommendation of the unblinded Data Safety Monitoring Board. Clinical response rates at day 14 in the MRSA population (n = 97) were 50.0% (exebacase + antibiotics; 32/64) versus 60.6% (antibiotics alone; 20/33) (P = .392). Overall, rates of adverse events were similar across groups. No adverse events of hypersensitivity related to exebacase were reported. CONCLUSIONS: Exebacase + antibiotics failed to improve clinical response at day 14 in patients with MRSA bacteremia/endocarditis. This result was unexpected based on phase 2 data that established proof-of-concept for exebacase + antibiotics in patients with MRSA bacteremia/endocarditis. In the antibiotics-alone group, the clinical response rate was higher than that seen in phase 2. Heterogeneity within the study population and a relatively small sample size in either the phase 2 or phase 3 studies may have increased the probability of imbalances in the multiple components of day 14 clinical outcome. This study provides lessons for future superiority studies in S. aureus bacteremia/endocarditis. Clinical Trials Registration.NCT04160468.
Subject(s)
Anti-Bacterial Agents , Bacteremia , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Humans , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Male , Female , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/administration & dosage , Middle Aged , Bacteremia/drug therapy , Bacteremia/microbiology , Aged , Methicillin-Resistant Staphylococcus aureus/drug effects , Adult , Endocarditis, Bacterial/drug therapy , Endocarditis, Bacterial/microbiology , Treatment Outcome , Standard of Care , Drug Therapy, Combination , Staphylococcus aureus/drug effectsABSTRACT
Human herpesvirus 6B (HHV-6B) frequently reactivates after allogeneic hematopoietic cell transplantation (HCT). There are no randomized studies of antiviral treatments to prevent HHV-6B reactivation. Brincidofovir has high in vitro activity against HHV-6B and other DNA viruses, but its in vivo activity for HHV-6B has not been demonstrated. We performed a post hoc analysis of a randomized controlled trial of twice-weekly oral brincidofovir for cytomegalovirus prophylaxis after allogeneic HCT to study the effect of brincidofovir on HHV-6B reactivation. We included patients randomized within 2 weeks of HCT and who received at least 6 consecutive doses of study drug after randomization. We tested plasma for HHV-6B through week 6 post-HCT. The cohort consisted of 92 patients receiving brincidofovir and 61 receiving placebo. The cumulative incidence of HHV-6B plasma detection through day 42 post-HCT was significantly lower among patients receiving brincidofovir (14.2%) compared with placebo (32.4%; log-rank, 0.019). In an adjusted Cox model, brincidofovir exposure remained associated with a lower hazard for HHV-6B plasma detection (hazard ratio, 0.40; 95% confidence interval, 0.20-0.80). In conclusion, brincidofovir prophylaxis reduced HHV-6B reactivation after allogeneic HCT in a post hoc analysis of a randomized controlled trial. These data support the study of intravenous brincidofovir for HHV-6B prophylaxis.
Subject(s)
Cytosine/analogs & derivatives , Graft vs Host Disease/drug therapy , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Herpesvirus 6, Human/isolation & purification , Organophosphonates/administration & dosage , Roseolovirus Infections/drug therapy , Viremia/drug therapy , Administration, Oral , Adolescent , Adult , Aged , Antiviral Agents/administration & dosage , Cohort Studies , Cytosine/administration & dosage , DNA, Viral , Female , Follow-Up Studies , Graft vs Host Disease/epidemiology , Graft vs Host Disease/etiology , Hematologic Neoplasms/pathology , Humans , Incidence , Male , Middle Aged , Prognosis , Randomized Controlled Trials as Topic , Roseolovirus Infections/epidemiology , Roseolovirus Infections/etiology , United States/epidemiology , Viral Load , Viremia/epidemiology , Viremia/etiology , Virus Activation , Young AdultABSTRACT
Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.
Subject(s)
Cytomegalovirus Infections/prevention & control , Cytomegalovirus , Cytosine/analogs & derivatives , Hematopoietic Stem Cell Transplantation , Organophosphonates/administration & dosage , Administration, Oral , Adolescent , Adult , Aged , Allografts , Cytomegalovirus Infections/etiology , Cytomegalovirus Infections/mortality , Cytosine/administration & dosage , Cytosine/adverse effects , Disease-Free Survival , Female , Humans , Male , Middle Aged , Organophosphonates/adverse effects , Survival RateABSTRACT
High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count <500/µL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 10(9) granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P > .99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 10(9) granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393.
Subject(s)
Granulocytes/cytology , Infections/complications , Leukocyte Transfusion/methods , Neutropenia/complications , Neutropenia/therapy , Anti-Infective Agents/therapeutic use , Dexamethasone/pharmacology , Glucocorticoids/pharmacology , Granulocyte Colony-Stimulating Factor/pharmacology , Granulocytes/drug effects , Humans , Infections/drug therapy , Leukocyte Count , Treatment OutcomeABSTRACT
BACKGROUND: Optimal prevention of late cytomegalovirus (CMV) disease is poorly defined. OBJECTIVE: To compare valganciclovir prophylaxis with polymerase chain reaction-guided preemptive therapy. DESIGN: Randomized, double-blind trial. (ClinicalTrials.gov: NCT00016068). SETTING: Multicenter trial. PATIENTS: 184 recipients of hematopoietic cell transplantation (HCT) who were at high risk for late CMV disease (95 patients received valganciclovir and 89 received placebo). INTERVENTION: 6 months of valganciclovir (900 mg/d) or placebo. Patients with polymerase chain reaction positivity at 1000 copies/mL or greater or a 5-fold increase over baseline were treated with ganciclovir or valganciclovir (5 mg/kg or 900 mg twice daily, respectively). MEASUREMENTS: The composite primary end point was death, CMV disease, or other invasive infections by 270 days after HCT. Secondary end points were CMV disease, CMV DNAemia, death, other infections, resource utilization, ganciclovir resistance, quality of life, immune reconstitution, and safety. RESULTS: The primary composite outcome occurred in 20% of valganciclovir recipients versus 21% of placebo-preemptive therapy recipients (treatment difference, -0.01 [95% CI, -0.13 to 0.10]; P = 0.86). There was no difference in the primary end point or its components 640 days after HCT. The incidence of a CMV DNAemia level of 1000 copies/mL or greater or a 5-fold increase over baseline was reduced in the valganciclovir group (11% vs. 36%; P < 0.001). Neutropenia was not significantly different at the absolute neutrophil count of less than 0.5 × 109 cells/L (P = 0.57); however, more patients received hematopoietic growth factors in the valganciclovir group (25.3% vs. 12.4%; P = 0.026). No significant differences were seen in other secondary outcomes. LIMITATION: Some high-risk patients were not included. CONCLUSION: Valganciclovir prophylaxis was not superior in reducing the composite end point of CMV disease, invasive bacterial or fungal disease, or death when compared with polymerase chain reaction-guided preemptive therapy. Both strategies performed similarly with regard to most clinical outcomes. PRIMARY FUNDING SOURCE: Roche Laboratories.
Subject(s)
Antiviral Agents/therapeutic use , Cytomegalovirus Infections/prevention & control , Ganciclovir/analogs & derivatives , Hematopoietic Stem Cell Transplantation/adverse effects , Adolescent , Adult , Aged , Antiviral Agents/adverse effects , Cytomegalovirus/genetics , Cytomegalovirus Infections/immunology , DNA, Viral/blood , Double-Blind Method , Female , Follow-Up Studies , Ganciclovir/adverse effects , Ganciclovir/therapeutic use , Humans , Immunity, Cellular , Male , Middle Aged , Neutropenia/chemically induced , Polymerase Chain Reaction , Quality of Life , Treatment Outcome , Valganciclovir , Young AdultABSTRACT
Though several antivirals have been developed and marketed to treat influenza virus infections, the development of antiviral agents with clinical activity against other respiratory viruses has been more problematic. Here we review the epidemiology of respiratory viral infections in immunocompetent and immunocompromised hosts, examine the evidence surrounding the currently available antivirals for respiratory viral infections other than influenza, highlight those that are in the pipeline, and discuss the hurdles for development of such agents.
Subject(s)
Antiviral Agents/therapeutic use , Bronchial Diseases/prevention & control , Respiratory Tract Infections/drug therapy , Virus Diseases/drug therapy , Antiviral Agents/pharmacology , Bronchial Diseases/diagnosis , Bronchial Diseases/economics , Bronchial Diseases/microbiology , Bronchial Diseases/therapy , Community-Acquired Infections/drug therapy , Community-Acquired Infections/prevention & control , Humans , Respiratory Tract Infections/virologyABSTRACT
BK polyomavirus (BKPyV) has been associated with hemorrhagic cystitis (HC) after allogeneic hematopoietic cell transplantation (HCT), but the natural history of HC and factors associated with the clinical course are incompletely understood. We retrospectively analyzed allogeneic HCT patients transplanted from 2007-2017 who presented after platelet engraftment or after day 28 post-HCT with BKPyV-associated HC (BKPyV-HC), which was defined as a positive urine BKPyV PCR, ≥1 plasma BKPyV viral load result, and macroscopic hematuria (Bedi grade ≥2). Factors associated with resolution of macroscopic hematuria and resolution of all cystitis symptoms within 90 days after HC diagnosis were investigated in multivariable models. In 128 patients with BKPyV-HC, the median times from diagnosis to resolution of all symptoms, macroscopic hematuria, and urinary clots (present in 55% [71/128]) were 24 days (15-44), 17 days (10-30), and 14 days (5-26), respectively. Ninety percent of patients had BKPyV viremia at the onset of HC with a median viral load of 1850 copies/mL (interquartile range, 240-8550). In multivariable models, high plasma viral load (≥10 000 copies/mL) and cytopenias at the beginning of BKPyV-HC were significantly associated with longer macroscopic hematuria and cystitis symptoms. Use of cidofovir was not associated with shorter duration of illness. In conclusion, BKPyV-HC after allogeneic HCT is characterized by prolonged and severe symptoms and requires improved management strategies. High-grade viremia and cytopenias were associated with a longer duration of BKPyV-associated HC. Accurate descriptions of disease and factors associated with prolonged recovery will inform end points of future clinical trials.
Subject(s)
BK Virus , Cystitis , Hematopoietic Stem Cell Transplantation , Polyomavirus Infections , Cystitis/diagnosis , Cystitis/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Polyomavirus Infections/diagnosis , Retrospective StudiesABSTRACT
BACKGROUND: APV102002 was an open-label study comparing a dual-boosted HIV-1 protease inhibitor (PI) [fosamprenavir/lopinavir/ritonavir (FPV/LPV/RTV; 1400 mg/533 mg/133 mg twice daily)] and a high dose of FPV/RTV 1400 mg/100 mg twice daily (HD-FPV/RTV) versus the standard FPV/RTV 700 mg/100 mg twice-daily (STD-FPV/RTV) regimen for 24 weeks. METHODS: Adult patients with prior failure to two or more PI-based regimens and on a failing PI regimen were randomized to STD-FPV/RTV (n = 24), HD-FPV/RTV (n = 25) or FPV/LPV/RTV (n = 25). The primary aim was to test week 24 superiority of HD-FPV/RTV and FPV/LPV/RTV over STD-FPV/RTV as measured by plasma HIV-1 RNA average area under the curve minus baseline (AAUCMB). RESULTS: There was no difference in the week 24 AAUCMB between the regimens. The proportion of patients with <50 copies/mL of plasma HIV RNA was 21%, 24% and 20%, respectively, by time to loss of virological response (TLOVR) analysis. High baseline drug resistance provided some explanation for the low efficacy. A lower baseline background drug resistance and higher fosamprenavir genotypic inhibitory quotient led to better antiviral responses. The plasma amprenavir trough concentartion (C(tau)) was 49% higher in the HD-FPV/RTV arm than in the STD-FPV/RTV arm and similar in the FPV/LPV/RTV and STD-FPV/RTV arms. The plasma lopinavir C(tau) was similar to historical data with standard LPV/RTV 400 mg/100 mg twice daily. All regimens were relatively well tolerated, although diarrhoea was more frequent in the HD-FPV/RTV and FPV/LPV/RTV arms, and hypertriglyceridaemia and increased total cholesterol were more common in the FPV/LPV/RTV arm. CONCLUSIONS: While the strategies of higher dose FPV/RTV and dual FPV/LPV/RTV were relevant at the time of study initiation, new therapies for antiretroviral-experienced patients make such strategies of limited interest. In addition, this study failed to demonstrate antiviral superiority of the HD-FPV/RTV or FPV/LPV/RTV regimen over the STD-FPV/RTV twice-daily regimen in highly treatment-experienced patients.
Subject(s)
Anti-HIV Agents/therapeutic use , Carbamates/therapeutic use , Drug Resistance, Viral , HIV Infections/drug therapy , HIV-1/drug effects , Organophosphates/therapeutic use , Ritonavir/therapeutic use , Sulfonamides/therapeutic use , Adult , Aged , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Carbamates/administration & dosage , Carbamates/adverse effects , Female , Furans , HIV Infections/virology , Humans , Male , Middle Aged , Organophosphates/administration & dosage , Organophosphates/adverse effects , Ritonavir/administration & dosage , Ritonavir/adverse effects , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Treatment Outcome , Viral LoadABSTRACT
BACKGROUND: Oseltamivir is safe and effective in immunocompetent persons, and prophylactic use is recommended during influenza outbreaks. However, no data exist regarding the use of oseltamivir as prophylaxis among patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: In January 2002, an influenza A outbreak was identified when 4 cases occurred within 1 week at an outpatient residential facility for patients undergoing HSCT. Oseltamivir prophylaxis (75 mg per day) was initiated for all asymptomatic patients living in the housing facility. Retrospectively, 45 patients (25 of whom had undergone HSCT, and 20 of whom were pre-HSCT candidates) who received oseltamivir prophylaxis were evaluated for adverse events. These 45 patients were matched 1 : 1 with control subjects who received transplants during the period 1994-2003 and did not receive prophylaxis; they were matched according to donor type, conditioning regimen, cytomegalovirus serostatus, time after HSCT, and recipient age (+/-5 years). The frequency of clinical and laboratory adverse events was determined by chart review and graded using National Cancer Institute Common Terminology Criteria. RESULTS: Forty-five residents received oseltamivir for a median of 17 days (range, 10-81 days). No new cases of influenza A occurred in the facility. Seven weeks after initiation of prophylaxis, 1 resident who had been noncompliant to prophylaxis developed an influenza B infection, followed by an additional case of influenza B that occurred in a patient who had not received prophylaxis. No deaths occurred that were attributable to prophylaxis. The proportions of clinical and laboratory adverse events meeting common terminology criteria grades 2-4 or 3-4 were not significantly different between the case patients who received oseltamivir prophylaxis and control subjects. CONCLUSION: Oseltamivir prophylaxis appeared to be safe and well tolerated in managing an influenza outbreak in an HSCT outpatient residence.
Subject(s)
Antiviral Agents/therapeutic use , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Influenza, Human/prevention & control , Oseltamivir/therapeutic use , Adolescent , Adult , Aged , Antiviral Agents/adverse effects , Case-Control Studies , Child , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Graft Rejection , Graft Survival , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/immunology , Humans , Immunocompromised Host , Influenza, Human/immunology , Male , Middle Aged , Oseltamivir/adverse effects , Probability , Reference Values , Retrospective Studies , Risk Assessment , Treatment OutcomeABSTRACT
BACKGROUND: Human metapneumovirus (hMPV), a recently discovered respiratory virus, is associated with clinical disease in young and elderly persons. OBJECTIVE: To determine the importance of hMPV in hematopoietic stem-cell transplant recipients. DESIGN: Retrospective survey of patients with consecutive residual bronchoalveolar lavage (BAL) samples. SETTING: Referral cancer center. PATIENTS: Hematopoietic stem-cell transplant recipients who underwent BAL because of lower respiratory tract disease. MEASUREMENTS: Bronchoalveolar lavage specimens were assayed by quantitative real-time polymerase chain reaction methods. RESULTS: Human metapneumovirus was detected in BAL specimens from 5 of 163 patients (3.0%). Persistent viral infection was noted in 3 patients with several samples, and hMPV was detected in 1 of 2 lung specimens tested. Infected patients became symptomatic within the first 40 days after transplantation. Initial symptoms included fever, cough, nasal congestion, and sore throat. Clinical findings included respiratory failure, pulmonary hemorrhage, and culture-negative septic shock. Four of 5 patients died with acute respiratory failure. LIMITATIONS: This retrospective study did not evaluate asymptomatic patients or those with mild disease. CONCLUSION: Human metapneumovirus infection in the lower respiratory tract is associated with respiratory failure in immunocompromised adults who were previously considered to have "idiopathic pneumonia." The infection may result in fulminant respiratory decompensation and shock after transplantation.
Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Immunocompromised Host , Metapneumovirus , Paramyxoviridae Infections/etiology , Pneumonia, Viral/etiology , Adrenal Cortex Hormones/therapeutic use , Adult , Antiviral Agents/therapeutic use , Bone Marrow Transplantation/adverse effects , Bone Marrow Transplantation/immunology , Bronchoalveolar Lavage , Female , Humans , Male , Metapneumovirus/isolation & purification , Middle Aged , Paramyxoviridae Infections/drug therapy , Pneumonia, Viral/drug therapy , Prognosis , Retrospective Studies , Ribavirin/therapeutic useABSTRACT
Brincidofovir (BCV, CMX001) is an orally available, long-acting, broad-spectrum antiviral that has been evaluated in healthy subjects in Phase I studies and in hematopoietic cell transplant recipients and other immunocompromised patients in Phase II/III clinical trials for the prevention and treatment of cytomegalovirus and adenovirus infections. BCV has also shown in vitro activity against orthopoxviruses such as variola (smallpox) virus, and is under advanced development as a treatment for smallpox under the US FDA's 'Animal Rule'. The anticipated treatment regimen for smallpox is a total weekly dose of 200 mg administered orally for 3 consecutive weeks. To assess the benefit-to-risk profile of BCV for the treatment of smallpox, we evaluated short-term safety data associated with comparable doses from Phase I studies and from adult and pediatric subjects in the cytomegalovirus and adenovirus clinical programs. When administered at doses and durations similar to that proposed for the treatment of smallpox, BCV was generally well tolerated in both adults and pediatric subjects. The most common adverse events were mild gastrointestinal events and asymptomatic, transient, and reversible elevations in serum transaminases. The data presented herein indicate a favorable safety profile for BCV for the treatment of smallpox, and support its continued development for this indication.
Subject(s)
Cytosine/analogs & derivatives , Organophosphonates/administration & dosage , Organophosphonates/pharmacology , Smallpox/drug therapy , Adenoviridae/drug effects , Adolescent , Adult , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Cytomegalovirus/drug effects , Cytosine/administration & dosage , Cytosine/pharmacology , Disease Models, Animal , Double-Blind Method , Drug Administration Schedule , Humans , Middle Aged , Orthopoxvirus/drug effects , Safety , Young AdultABSTRACT
Primary cytomegalovirus (CMV) infection is usually asymptomatic in immunocompetent patients but can cause serious life-threatening complications in immunocompromised CMV-seronegative patients, including patients receiving a bone marrow or peripheral blood stem cell transplant, recipients of some solid-organ transplants, and low-birth-weight neonates. Current recommendations for preventing transfusion-transmitted CMV (TT-CMV) infection in these patients include exclusive use of CMV-seronegative and/or leukoreduced cellular blood components (red blood cells and platelets) for transfusion. However, breakthrough cases of TT-CMV still occur. Despite improving the safety of blood components, testing remains a reactive approach to blood safety. In contrast, pathogen inactivation technologies offer a proactive approach with the potential to further improve blood safety. To reduce the risks associated with platelet transfusions, a photochemical treatment (PCT) process using a combination of the psoralen amotosalen HCl and long-wavelength UV light has been developed and introduced into clinical practice in Europe. PCT has been shown to result in greater than 5.9-log reductions in infectivity of human CMV in platelet concentrates and to prevent the transfusion transmission of murine CMV in a mouse transfusion model. Thus, PCT pathogen inactivation may play a role in further reducing the incidence of TT-CMV infection in patients who are at risk for serious CMV disease. Because PCT is a technology that targets nucleic acids, it also offers a proactive process for the inactivation of a broad range of viral, bacterial, and protozoan pathogens in addition to CMV.
Subject(s)
Blood Component Transfusion , Cytomegalovirus Infections/prevention & control , Photochemotherapy , Photosensitizing Agents/pharmacology , Virus Inactivation , Animals , Female , Furocoumarins/pharmacology , Humans , Male , Mice , Photochemotherapy/methods , Ultraviolet RaysABSTRACT
PURPOSE: The logistics of conducting double-blinded phase III clinical trials with participants residing in remote locations are complex. Here we describe the implementation of an interventional trial for the prevention of late cytomegalovirus (CMV) disease in hematopoietic cell transplantation (HCT) subjects in a long-term follow-up environment. METHODS: A total of 184 subjects at risk for late CMV disease surviving 80 days following allogeneic HCT were randomized to receive six months of valganciclovir or placebo. Subjects were followed through day 270 post-transplant at their local physician's office within the United States. Anti-viral treatment interventions were based on CMV DNAemia as measured by polymerase chain reaction (PCR) (>1000 copies/mL) and granulocyte colony stimulating factor (G-CSF) was prescribed for neutropenia (absolute neutrophil count (ANC <1.0 × 109 cells/L). Blood samples for viral testing and safety monitoring were shipped to a central laboratory by overnight carrier. Real-time communication was established between the coordinating center and study sites, primary care physicians, and study participants to facilitate starting, stopping and dose adjustments of antiviral drugs and G-CSF. The time required to make these interventions was analyzed. RESULTS: Of the 4169 scheduled blood specimens, 3832 (92%) were received and analyzed; the majority (97%) arriving at the central site within 2 days. Among subjects with positive CMV DNAemia (N=46), over 50% received open label antiviral medication within one day. The median time to start G-CSF for neutropenia was <1 day after posting of laboratory results (range 0-6; N=38). Study drug dose adjustments for abnormal renal function were implemented 203 times; within one day for 48% of cases and within 2 days for 80% of cases. CONCLUSION: Complex randomized, double-blind, multicenter interventional trials with treatment decisions made at a central coordinating site can be conducted safely and effectively according to Good Clinical Practice (GCP) guidelines over a large geographic area.
ABSTRACT
OBJECTIVES: Dolutegravir (DTG) has been studied in three trials in HIV treatment-naive participants, showing noninferiority compared with raltegravir (RAL), and superiority compared with efavirenz and ritonavir-boosted darunavir. We explored factors that predicted treatment success, the consistency of observed treatment differences across subgroups and the impact of NRTI backbone on treatment outcome. DESIGN: Retrospective exploratory analyses of data from three large, randomized, international comparative trials: SPRING-2, SINGLE, and FLAMINGO. METHODS: We examined the efficacy of DTG in HIV-infected participants with respect to relevant demographic and HIV-1-related baseline characteristics using the primary efficacy endpoint from the studies (FDA snapshot) and secondary endpoints that examine specific elements of treatment response. Regression models were used to analyze pooled data from all three studies. RESULTS: Snapshot response was affected by age, hepatitis co-infection, HIV risk factor, baseline CD4⺠cell count, and HIV-1 RNA and by third agent. Differences between DTG and other third agents were generally consistent across these subgroups. There was no evidence of a difference in snapshot response between abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) overall [ABC/3TC 86%, TDF/FTC 85%, difference 1.1%, confidence interval (CI) -1.8, 4.0 percentage points, Pâ=â0.61] or at high viral loads (difference -2.5, 95% CI -8.9, 3.8 percentage points, Pâ=â0.42). CONCLUSIONS: DTG is a once-daily, unboosted integrase inhibitor that is effective in combination with either ABC/3TC or TDF/FTC for first-line antiretroviral therapy in HIV-positive individuals with a variety of baseline characteristics.
Subject(s)
Anti-HIV Agents/therapeutic use , Dideoxynucleosides/therapeutic use , HIV Infections/drug therapy , Heterocyclic Compounds, 3-Ring/therapeutic use , Lamivudine/therapeutic use , Adenine/analogs & derivatives , Adenine/therapeutic use , Adult , Antiretroviral Therapy, Highly Active/methods , CD4 Lymphocyte Count , Clinical Trials, Phase III as Topic , Coinfection , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Drug Combinations , Emtricitabine , Female , HIV Integrase Inhibitors/therapeutic use , HIV Protease Inhibitors/therapeutic use , HIV-1 , Humans , Male , Organophosphonates/therapeutic use , Oxazines , Piperazines , Pyridones , Pyrrolidinones/therapeutic use , Raltegravir Potassium , Randomized Controlled Trials as Topic , Regression Analysis , Retrospective Studies , Ritonavir/therapeutic use , Tenofovir , Treatment Outcome , Viral LoadABSTRACT
BACKGROUND: Community-acquired respiratory viruses, such as influenza virus, are thought to be major causes of morbidity and mortality in patients who had undergone hematopoietic stem cell transplantation (HSCT). Risk factors for acquisition, progression to pneumonia, and the effect of antiviral therapy are unknown. METHODS: We reviewed records from patients with documented influenza over 12 consecutive respiratory-virus infection seasons at a single transplantation center. RESULTS: From 1 September 1989 through 31 March 2002, influenza virus was isolated from 62 of 4797 persons undergoing HSCT (1.3%); 44 patients had upper respiratory tract infections (URIs) alone, and 18 developed pneumonia. Among patients with influenza virus infection, pneumonia developed more commonly among those infected earlier after transplantation (median, 36 vs. 61 days, P=.04) and those with concurrent lymphopenia. Of the 51 cases that were initially diagnosed as URIs, 17 were treated with antivirals, and 34 were not treated. Six untreated patients (18%) developed pneumonia, whereas 1 (13%) of 8 patients treated with rimantadine and 0 of 9 treated with oseltamivir developed pneumonia. The duration of influenza virus shedding was longer in patients treated with steroid doses of >1 mg/kg than among those treated with doses of <1 mg/kg (mean, 15 vs. 9 days); there was a trend towards decreased shedding with oseltamivir therapy (but not rimantadine therapy) after controlling for steroid use (P<.08). The 30-day mortality rate was highest among patients who had progression to pneumonia (5 [28%] of 18 patients); pulmonary copathogens (such as Aspergillus fumigatus) were commonly isolated. CONCLUSIONS: Influenza virus infection is an important cause of mortality early after HSCT. Our nonrandomized data suggest that early antiviral therapy with neuraminidase inhibitors may prevent progression to pneumonia and decrease viral shedding, which may prevent both influenza-related death in index patients and nosocomial transmission to others.
Subject(s)
Antiviral Agents/therapeutic use , Hematopoietic Stem Cell Transplantation , Influenza, Human/drug therapy , Influenza, Human/mortality , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Infant , Influenza, Human/virology , Male , Middle Aged , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/virology , Retrospective Studies , Risk Factors , Washington/epidemiologyABSTRACT
Infections with a diverse group of microorganisms remain the leading causes of morbidity and mortality after hematopoietic stem cell transplantation. Importantly, the epidemiology of infectious complications has shifted substantially with changes in antimicrobial prophylaxis, conditioning regimens and graft manipulation, such that invasive mould infections and late viral infections are now the over-riding concerns. New antivirals and antifungals have entered clinical practice and hold considerable promise for improved outcomes.
Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Infections/drug therapy , Bacterial Infections/drug therapy , Humans , Mycoses/drug therapy , Neutropenia/drug therapy , Virus Diseases/drug therapySubject(s)
Ganciclovir/analogs & derivatives , Hematopoietic Stem Cell Transplantation/adverse effects , Immunocompromised Host , Mycoses/etiology , Opportunistic Infections/etiology , Antiviral Agents/therapeutic use , Cytomegalovirus Infections/drug therapy , Ganciclovir/therapeutic use , Graft vs Host Disease/complications , Humans , Mycoses/prevention & control , Opportunistic Infections/prevention & control , ValganciclovirABSTRACT
BACKGROUND: Between August 1 and October 30, 1998 (outbreak period), an increased incidence of central venous catheter (CVC)-associated gram-negative bacterial bloodstream infection (GN-BSI) was detected in hematopoietic stem cell transplantation (HSCT) candidates and recipients in an outpatient HSCT unit. The objectives of the present study were to determine strategies for controlling the outbreak and identify risk factors for GN-BSI. METHODS: Two case-control studies, an assessment of infection control practices, microbiologic studies, and water quality analysis were conducted. A case was defined as any outpatient with a CVC and a primary GN-BSI during the outbreak period. RESULTS: All of the 31 case patients identified had needleless intravenous (IV) access devices. Independent risk factors for CVC-associated GN-BSI were self-administered IV infusion (odds ratio [OR] = 6.2; P = .02), lower frequency of needleless device changes (OR = 15.2; P = .03), and more frequent baths (OR = 1.4; P = .05). Interventions included increased frequency of needleless device change, recommending showers rather than baths, and use of CVC protection during showering/bathing. After these interventions, the CVC-associated GN-BSI rate declined to below the preoutbreak period rate (2.1/1000 vs 0.3/1000 CVC-days; P < .01). CONCLUSIONS: This study demonstrated an increased risk of CVC-associated GN-BSIs related to self-IV infusion, bathing habits, and frequency of needleless device change. Infection control practices associated with the use of needleless devices may expose susceptible patients to increased risk for BSI.
Subject(s)
Catheterization, Central Venous/adverse effects , Cross Infection/epidemiology , Gram-Negative Bacteria/isolation & purification , Gram-Negative Bacterial Infections/epidemiology , Infection Control , Infusions, Intravenous/adverse effects , Adolescent , Adult , Aged , Balneology , Case-Control Studies , Catheterization, Central Venous/instrumentation , Catheterization, Central Venous/methods , Catheters, Indwelling/adverse effects , Child , Child, Preschool , Disease Outbreaks , Female , Gram-Negative Bacterial Infections/microbiology , Gram-Negative Bacterial Infections/prevention & control , Humans , Incidence , Infant , Infusions, Intravenous/instrumentation , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Risk Factors , Self Care/adverse effects , United States/epidemiology , Young AdultABSTRACT
We conducted a 12-year retrospective study to determine the effects that the community respiratory-virus species and the localization of respiratory-tract virus infection have on severe airflow decline, a serious and fatal complication occurring after hematopoietic cell transplantation (HCT). Of 132 HCT recipients with respiratory-tract virus infection during the initial 100 days after HCT, 50 (38%) developed airflow decline < or =1 year after HCT. Lower-respiratory-tract infection with parainfluenza (odds ratio [OR], 17.9 [95% confidence interval {CI}, 2.0-160]; P=.01) and respiratory syncytial virus (OR, 3.6 [95% CI, 1.0-13]; P=.05) independently increased the risk of development of airflow decline < or =1 year after HCT. The airflow decline was immediately detectable after infection and was strongest for lower-respiratory-tract infection with parainfluenza virus; it stabilized during the months after the respiratory-tract virus infection, but, at < or =1 year after HCT, the initial lung function was not restored. Thus, community respiratory virus-associated airflow decline seems to be specific to viral species and infection localization.
Subject(s)
Community-Acquired Infections/virology , Hematopoietic Stem Cell Transplantation , Pulmonary Ventilation , Respiratory Tract Infections/virology , Adult , Community-Acquired Infections/physiopathology , Cytomegalovirus Infections/physiopathology , Female , Humans , Male , Middle Aged , Paramyxoviridae Infections/physiopathology , Pneumonia, Viral/physiopathology , Respiratory Syncytial Virus Infections/physiopathology , Respiratory Tract Infections/physiopathology , Retrospective Studies , Risk Factors , Transplantation, HomologousABSTRACT
Actinomycetes are increasingly recognized as pathogenic in the immunocompromised host. We isolated an asporogenous, nonmotile, aerobic gram-positive rod from a transplant recipient with a fatal pulmonary infection. The pathology was similar to that associated with Rhodococcus equi, including intra-histiocytic localization. The organism was relatively inert in standard biochemical tests. 16S rRNA gene sequencing indicated a potentially unique organism most closely related to the genus Streptomyces, for which we propose the name "Para-streptomyces abscessus."