BackgroundPreclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.Methods30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.ResultsA significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid Emax pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.ConclusionsTenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy.Trial RegistrationClinicalTrials.gov NCT00594373
BackgroundThe pharmacokinetics and pharmacodynamics of vaginal microbicides are typically assessed among sexually abstinent women. However, the physical act of sex may modulate gel distribution, and preclinical studies demonstrate seminal plasma interferes with the antiviral activity of several microbicides. This study compared the biological activity and concentration of PRO 2000 in cervicovaginal lavage (CVL) collected in the absence or following coitus.MethodsCVL samples were collected from ten heterosexual couples at baseline, after sex, after a single dose of 0.5% PRO 2000 gel and sex, and after gel application without sex. The impact of CVL on HIV-1 infection of TZM-bl cells and HSV-2 infection of CaSki cells was monitored by luciferase and plaque assay, respectively. PRO 2000 concentrations were measured by fluorescence.ResultsCVL collected after PRO 2000 application significantly inhibited HIV-1 and HSV-2 (p = 0.01). However, the antiviral activity was reduced following sex and no significant protective effect was observed in postcoital CVL obtained in the presence compared to the absence of PRO 2000 for HIV (p = 0.45) or HSV-2 (p = 0.56). Less PRO 2000 was recovered in postcoital CVL, which, in conjunction with interference by seminal plasma, may have contributed to lower antiviral activity.ConclusionsPostcoital responses to PRO 2000 differ from precoital measures and the results obtained may provide insights into the clinical trial findings in which there was no significant protection against HIV-1 or HSV-2. Postcoital studies should be incorporated into clinical studies before embarking on large-scale efficacy trials.
These results suggest that a hybrid preventative approach for CMV is a reasonable alternative to prolonged antiviral prophylaxis and may reduce unnecessary exposure to antiviral therapy. However, patients who receive intensified immunosuppression after acute rejection are at increased risk for CMV and may require extended prophylaxis and closer monitoring.
Results of this multicenter cohort study suggest that H-RVIs are relatively common in pediatric HSCT recipients and contribute to significant morbidity and death. These data should help inform interventional studies specific to each viral pathogen.
BackgroundFemale genital tract secretions are bactericidal for Escherichia (E.) coli ex vivo. However, the intersubject variability and molecules that contribute to this activity have not been defined.MethodsThe bactericidal activity and concentration of immune mediators in cervicovaginal lavage (CVL) collected from 99 healthy women were determined.ResultsCVL reduced the number of E. coli colonies by 68% [−26, 100] (median [range]). CVL were active against laboratory and clinical isolates of E. coli, but were inactive against Lactobacillus species. Bactericidal activity correlated with the concentration of protein recovered (p<0.001), but not with cytokines, chemokines or antimicrobial peptides. Four CVL with>90% inhibitory activity (active) and two with<30% activity were subjected to MS/MS proteomic analysis. 215 proteins were identified and six were found exclusively in active samples. Four of these corresponded to Lactobacillus crispatus or jensenii proteins. Moreover, culture supernatants from Lactobacillus jensenii were bactericidal for E. coli.
ConclusionBoth host and commensal microbiota proteins contribute to mucosal defense. Identification of these proteins will facilitate the development of strategies to maintain a healthy vaginal microbiome and prevent colonization with pathogenic bacteria such as E. coli that increase the risk for urinary tract infections, preterm labor and perinatal infection.
These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of HHV‐6A, HHV‐6B, HHV‐7, and HHV‐8 in the pre‐ and post‐transplant period. The majority of HHV‐6 (A and B) and HHV‐7 infections in transplant recipients are asymptomatic; symptomatic disease is reported infrequently across organs. Routine screening for HHV‐6 and 7 DNAemia is not recommended in asymptomatic patients, nor is prophylaxis or preemptive therapy. Detection of viral nucleic acid by quantitative PCR in blood or CSF is the preferred method for diagnosis of HHV‐6 and HHV‐7 infection. The possibility of chromosomally integrated HHV‐6 DNA should be considered in individuals with persistently high viral loads. Antiviral therapy should be initiated for HHV‐6 encephalitis and should be considered for other manifestations of disease. HHV‐8 causes Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease and is also associated with hemophagocytic syndrome and bone marrow failure. HHV‐8 screening and monitoring may be indicated to prevent disease. Treatment of HHV‐8 related disease centers on reduction of immunosuppression and conversion to sirolimus, while chemotherapy may be needed for unresponsive disease. The role of antiviral therapy for HHV‐8 infection has not yet been defined.
We report 2 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) in infants presenting with fever in the absence of respiratory distress who required hospitalization for evaluation of possible invasive bacterial infections. The diagnoses resulted from routine isolation and real-time reverse-transcription polymerase chain reaction–based testing for SARS-CoV-2 for febrile infants in an outbreak setting.
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