Search

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1)., Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.)

Live-vector-based human immunodeficiency virus (HIV) vaccines are an integral part of a number of HIV vaccine regimens currently under evaluation. Live vectors that carry an intact gag gene are capable of eliciting HIV pseudovirion particle formation from infected host cells. The impact of pseudovirion particle formation on the immune response generated by live HIV vaccine vectors has not been established. In this study, a canarypox HIV vaccine candidate vector expressing HIV gag and env genes, vCP205, was modified by the introduction of a glycine-to-alanine coding change in the N-terminal myristylation site of gag to create Myr − vCP205. This substitution effectively eliminated particle formation without altering the level of protein production. vCP205 and Myr − vCP205 were then directly compared for the ability to induce HIV-specific immune responses in mice. The particle-competent vector vCP205 elicited higher levels of CD8 + T-cell responses, as indicated by gamma interferon enzyme-linked immunospot (ELISPOT) assay and intracellular cytokine staining. Humoral responses to Gag and Env were also markedly higher from animals immunized with the particle-competent vector. Furthermore, HIV-specific CD4 + T-cell responses were greater among animals immunized with the particle-competent vector. Using a human dendritic cell model of antigen presentation in vitro, vCP205 generated greater ELISPOT responses than Myr − vCP205. These results demonstrate that pseudovirion particle production by live-vector HIV vaccines enhances HIV-specific cellular and humoral immune responses.

Structured treatment interruptions (STIs) have been proposed as a potential treatment strategy during human immunodeficiency virus type 1 (HIV-1) antiretroviral therapy. This still-experimental intervention requires a close monitoring of patients' plasma viremia and CD4 + -T-cell counts during the treatment interruption phase. By using signal amplification of a heat-dissociated p24 antigen (p24Ag) assay, we compared p24Ag levels with levels of HIV RNA in plasma. One hundred seventy-four plasma samples were obtained from 51 chronically HIV-infected patients: 117 from patients who underwent STIs and 57 from patients who did not. Partial immune complex dissociation and clearance of those complexes by the erythrocytes were also investigated. A significant association between the two assays was observed (β = 0.23, 95% confidence interval = 0.18, 0.28; P < 0.0001), but the association was smaller in the subset of samples from patients undergoing STIs. Moreover, discordant results and lack of longitudinal intrapatient correlation between levels of p24Ag and HIV-1 RNA were higher in this group. Incomplete immune complex dissociation and binding of those complexes to erythrocytes could be contributing factors involved in the diminished detection of p24Ag. Therefore, signal amplification of a heat-dissociated p24Ag had a positive association with current HIV RNA assays in a population-based analysis. However, it might not be sensitive enough to monitor longitudinal intrapatient viremia during STIs in patients with high CD4 + -T-cell counts potentially due to the production of high-affinity anti-p24 antibodies and clearance of immune complexes by erythrocytes.

Fluoroquinolone resistance in Mycobacterium tuberculosis can be conferred by mutations in gyrA or gyrB . The prevalence of resistance mutations outside the quinolone resistance-determining region (QRDR) of gyrA or gyrB is unclear, since such regions are rarely sequenced. M. tuberculosis isolates from 1,111 patients with newly diagnosed culture-confirmed tuberculosis diagnosed in Tennessee from 2002 to 2009 were screened for phenotypic ofloxacin resistance (>2 μg/ml). For each resistant isolate, two ofloxacin-susceptible isolates were selected: one with antecedent fluoroquinolone exposure and one without. The complete gyrA and gyrB genes were sequenced and compared with M. tuberculosis H37Rv. Of 25 ofloxacin-resistant isolates, 11 (44%) did not have previously reported resistance mutations. Of these, 10 had novel polymorphisms: 3 in the QRDR of gyrA , 1 in the QRDR of gyrB , and 6 outside the QRDR of gyrA or gyrB ; 1 did not have any gyrase polymorphisms. Polymorphisms in gyrA codons 1 to 73 were more common in fluoroquinolone-susceptible than in fluoroquinolone-resistant strains (20% versus 0%; P = 0.016). In summary, almost half of fluoroquinolone-resistant M. tuberculosis isolates did not have previously described resistance mutations, which has implications for genotypic diagnostic tests.

Persons with previous extrapulmonary tuberculosis have reduced peripheral blood mononuclear cell cytokine production and CD4+lymphocytes compared to persons with previous pulmonary tuberculosis or latent tuberculosis infection, but specific defects related toMycobacterium tuberculosisinfection of macrophages have not been characterized. The objective of this study was to further characterize thein vitroimmune responses toM. tuberculosisinfection in HIV-seronegative persons with previous extrapulmonary tuberculosis. Peripheral blood mononuclear cells were isolated from HIV-seronegative persons with previous extrapulmonary tuberculosis (n= 11), previous pulmonary tuberculosis (n= 21), latentM. tuberculosisinfection (n= 19), and uninfected tuberculosis contacts (n= 20). Experimental conditions includedM. tuberculosis-infected macrophages cultured with and without monocyte-depleted peripheral blood mononuclear cells. Concentrations of interleukin 1β (IL-1β), IL-4, IL-6, CXCL8 (IL-8), IL-10, IL-12p70, IL-17, CCL2 (monocyte chemoattractant protein 1), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) were measured by multiplex cytokine array. WhenM. tuberculosis-infected macrophages were cocultured with monocyte-depleted peripheral blood mononuclear cells, IFN-γ (P= 0.01), TNF-α (P= 0.04), IL-10 (P< 0.001), and IL-6 (P= 0.03) exhibited similar continua of responses, with uninfected persons producing the lowest levels, followed by extrapulmonary tuberculosis cases, pulmonary tuberculosis controls, and persons with latentM. tuberculosisinfection. A similar pattern was observed with CXCL8 (P= 0.04), IL-10 (P= 0.02), and CCL2 (P= 0.03) when monocyte-depleted peripheral blood mononuclear cells from the four groups were cultured alone. Persons with previous extrapulmonary tuberculosis had decreased production of several cytokines, both at rest and after stimulation withM. tuberculosis. Our results suggest that persons who develop extrapulmonary tuberculosis have a subtle global immune defect that affects their response toM. tuberculosisinfection.