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.
•Brincidofovir has potent antiviral activity in animal models of smallpox infection.•A 3-week treatment course is projected for the treatment of smallpox.•Safety data from clinical studies in healthy adults receiving relevant brincidofovir doses or dose intervals are described.•Three-week safety data from clinical trials in adult and pediatric patients treated for viral infections are summarized.•Short-term dosing (3 weeks) necessary for the treatment of smallpox appears to be safe and well tolerated.
In the current era of effective prophylactic and preemptive therapy, cytomegalovirus (CMV) is now a rare cause of early mortality after hematopoietic stem cell transplantation (HSCT). However, the ...ultimate goal of completely eliminating the impact of CMV on survival remains elusive. Although the direct effects of CMV (ie, CMV pneumonia) have been largely eliminated, several recent cohort studies show that CMV-seropositive transplant recipients and seronegative recipients of a positive graft appear to have a persistent mortality disadvantage when compared with seronegative recipients with a seronegative donor. Recipients of T-cell–depleted allografts and/or transplants from unrelated or HLA-mismatched donors seem to be predominantly affected. Reasons likely include both incomplete prevention of direct and indirect or immunomodulatory effects of CMV as well as consequences of drug toxicities. The effect of donor CMV serostatus on outcome remains controversial. Large multicenter cohort studies are needed to better define the subgroups of seropositive patients that may benefit from intensified prevention strategies and to define the impact of CMV donor serostatus in the era of high-resolution HLA matching. Prevention strategies may require targeting both the direct and indirect effects of CMV infection by immunologic or antiviral drug strategies.
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.
The impact of cytomegalovirus (CMV) serostatus (seropositive + or seronegative -) of the donor (D) and recipient (R) on mortality after allogeneic non-T cell-depleted stem cell transplantation (SCT) ...in the era of preemptive therapy was assessed among 1750 patients by means of multivariable Cox regression models. In an analysis that included only pre-SCT variables, D+/R+ and D+/R- patients had the highest risk for mortality. After neutropenia or the occurrence of CMV disease was controlled for, only D+/R- patients remained at a significantly higher risk for mortality. Mortality due to bacteremia or invasive fungal infection was higher among D+/R- (18.3%) than D-/R- (9.7%) patients (P < .001). Thus, CMV serostatus remains associated with mortality; neutropenia due to ganciclovir administration and CMV disease explain the association with mortality among seropositive recipients. However, in D+/R- subjects, mortality appears to be associated with bacterial and fungal infection, indicating a possible immunomodulatory effect of primary CMV infection that was undetected despite intensive monitoring.
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 ⩽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 ⩽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 ⩽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
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 × 109 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 × 109 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.
•Overall, no benefit of granulocyte transfusion therapy was observed, but the power of the study was reduced due to low accrual.•Post hoc secondary analysis suggested that patients receiving higher doses tended to have better outcomes than those receiving lower ones.
Human metapneumovirus (hMPV), a recently discovered respiratory virus, is associated with clinical disease in young and elderly persons.
To determine the importance of hMPV in hematopoietic stem-cell ...transplant recipients.
Retrospective survey of patients with consecutive residual bronchoalveolar lavage (BAL) samples.
Referral cancer center.
Hematopoietic stem-cell transplant recipients who underwent BAL because of lower respiratory tract disease.
Bronchoalveolar lavage specimens were assayed by quantitative real-time polymerase chain reaction methods.
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.
This retrospective study did not evaluate asymptomatic patients or those with mild disease.
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.
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.
Retrospective exploratory analyses of data from three large, randomized, international comparative trials: SPRING-2, SINGLE, and FLAMINGO.
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.
Snapshot response was affected by age, hepatitis co-infection, HIV risk factor, baseline CD4⁺ 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, P = 0.61 or at high viral loads (difference -2.5, 95% CI -8.9, 3.8 percentage points, P = 0.42).
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.
Optimal prevention of late cytomegalovirus (CMV) disease is poorly defined.
To compare valganciclovir prophylaxis with polymerase chain reaction-guided preemptive therapy.
Randomized, double-blind ...trial. (ClinicalTrials.gov: NCT00016068).
Multicenter trial.
184 recipients of hematopoietic cell transplantation (HCT) who were at high risk for late CMV disease (95 patients received valganciclovir and 89 received placebo).
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).
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.
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.
Some high-risk patients were not included.
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.
Roche Laboratories.
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