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Background: Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.Methods: We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.Results: Viruses containing PA/I38X substitutions were identified 3-9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.Conclusions: The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.Clinical Trial Registration: NCT02954354. [ABSTRACT FROM AUTHOR]

Background: Treatment of blood samples from hemorrhagic fever virus (HFV)-infected patients with 0.1% detergents has been recommended for virus inactivation and subsequent safe laboratory testing. However, data on virus inactivation by this procedure are lacking. Here we show the effect of this procedure on diagnostic test results and infectious Ebola virus (EBOV) titers.Methods: Serum and whole-blood samples were treated with 0.1% or 1% sodium dodecyl sulfate (SDS) or 0.1% Triton X-100 and assayed for clinical chemistry and malaria antigen detection. Infectious EBOV titers were determined in SDS-treated plasma and whole blood from EBOV-infected nonhuman primates (NHPs). Infectious titers of EBOV or herpes simplex virus type 1 (HSV-1) in detergents-treated cell culture medium containing various serum concentrations were determined.Results: Laboratory test results were not affected by 0.1% detergent treatment of blood samples, in contrast with 1% SDS treatment. However, 0.1% detergent treatment did not inactivate EBOV in blood samples from infected NHPs. Experiments with cell culture medium showed that virus inactivation by detergents is annulled at physiological serum concentrations.Conclusions: Treatment of blood samples with 0.1% SDS or Triton X-100 does not inactivate EBOV. Inactivation protocols for HFV should be validated with serum and whole blood. [ABSTRACT FROM AUTHOR]

Influenza infection results in substantial morbidity and mortality in hospitalized patients, including those who are immunocompromised or pregnant. Antiviral therapy likely provides considerable benefit to these patients, but few studies have been successfully conducted in these high-risk populations, and no drugs are specifically licensed for treating these subgroups. One of the key challenges facing novel antiviral drug development for influenza is determining the appropriate efficacy end points that would enable rapid regulatory approval for drug use in seriously ill patients, for whom risk-benefit assessments differ from those with uncomplicated illness. All available antiviral drugs currently affect viral replication, and respiratory tract viral titers correlate with both symptoms and measures of host inflammatory responses, including cytokine and chemokine expression that are likely responsible for many of the clinical symptoms. Consequently, we outline the evidence to support the use of primary virological end points in studies of antiviral agents involving patients who are hospitalized with severe influenza or those who are at high risk of severe and life-threatening disease. [ABSTRACT FROM AUTHOR]

Five pediatric patients with no history of immuno deficiency had a life-threatening course of varicella. Strikingly, natural killer (NK) cells were absent from the circulation in all children, and, despite active viral infection, up to 98% of the CD8+ cells were naive. Primary immunodeficiencies were excluded-NK cells and primed CD8+ cells reappeared in the circulation, granzymes were detectable in plasma early during infection, and no abnormalities could be detected in interleukin- 15 receptor function. Our data indicate that varicella-zoster virus (VZV) has a unique capability to seclude primed CD8+ cells and NK cells from the circulating lymphocyte pool. This may be the consequence of an overwhelming immune response to VZV that is influenced by factors such as infectious dose, age, and the presence of maternal antibodies during infancy. Because both homozygous twin sisters in the study had a severe course of varicella, particular genetic factors may contribute to severe varicella. [ABSTRACT FROM AUTHOR]

Immunity to childhood diseases is maintained for decades by mechanisms that, at present, are still unclear. We longitudinally studied immune responses in 16 adults exposed to children experiencing varicella (chicken pox). None of the individuals showed clinical signs of infection, and varicella-zoster virus (VZV) DNA could not be detected in peripheral blood or cultured from nasopharyngeal swabs. Exposure to VZV, however, induced expansion of antigen-specific CD4+ T cells in peripheral blood, with concomitant changes in cytotoxic CD8+ T cells and natural killer cells. VZV-specific memory CD4+ T cells were uniformly CD45RA and enriched for CD27-. The virus-specific cells produced interferon-γ, tumor necrosis factor-αd interleukin-2. These memory responses to VZV were compared with the primary immune responses of children experiencing varicella. VZV-specific memory CD4+ T cell responses largely resemble the primary immune response to VZV. [ABSTRACT FROM AUTHOR]

Zidovudine treatment preferentially benefits persons with only non-syncytium-inducing (NSI) human immunodeficiency virus type 1 (HIV-1) variants. To understand this differential efficacy, changes in cellular virus load, clonal composition of HIV-1 populations, and development of resistance-conferring reverse transcriptase mutations were studied in 17 persons initiating zidovudine therapy. Zidovudine treatment resulted in larger and more sustained decreases in cellular virus load in persons with NSI variants only compared with persons also carrying syncytium-inducing (SI) variants. Although the former group had a delayed emergence of resistance mutations, differences in initial responses between the 2 groups were independent of the emergence of resistance mutations. Changes in virus load in subjects also carrying SI variants were due mainly to loss of coexisting NSI virus. Resistance mutations emerged at similar rates in both coexisting variants. Data suggest that mechanisms other than drug resistance are necessary to completely explain the phenotypedependent benefit of zidovudine. [ABSTRACT FROM PUBLISHER]

The potential use of an alternating treatment strategy with nevirapine and zidovudine in prolonging the antiretroviral effects of nevirapine was evaluated. Ten human immunodeficiency virus type 1 (HIV-1)-infected p24 antigen-positive persons who had not received prior antiretroviral therapy were treated for 9–13 weeks with an alternating regimen of 1 week of nevirapine (200 mg/day) and 3 weeks of zidovudine (600 mg/day), Serum p24 antigen levels declined during the first week of nevirapine treatment (median, 59%); however, subsequent courses of nevirapine were characterized by rising p24 antigen levels, while antigen levels remained stable or declined during zidovudine treatment. Serum β2-microglobulin levels and CD4+ cell counts exhibited similar responses. HIV-1 isolates obtained from 2 patients revealed 40- and 1000-fold reductions in nevirapine sensitivity after 8 weeks. These findings demonstrate that alternating treatment with zidovudine and nevirapine does not prolong the effectiveness of nevirapine and does not prevent the development of nevirapine resistance. [ABSTRACT FROM PUBLISHER]