Search

Background Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. Methods In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. Findings From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). Interpretation When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. Funding US National Institutes of Health.

Background Deferral of antiretroviral therapy (ART) initiation until CD4 count < 350 cells/μL in people with CD4 > 500 increases risk of AIDS and serious non-AIDS (SNA) conditions. Evidence from randomized trials is lacking to assess the extent to which ongoing excess risk due to having deferred initiation is reduced once ART is initiated and viral load suppressed. Methods START randomized 4684 ART-naïve HIV+ adults with CD4 > 500 cells/μL to start ART immediately (IMM, n=2325) or defer ART until CD4 < 350 cells/μL or AIDS developed (DEF, n= 2359). In 2015 the study demonstrated a 57% reduction in the risk of the primary endpoint (AIDS, SNA or death) for IMM ART; all assigned to DEF were recommended to start ART. Follow up continued to 31Dec2021. To determine whether the benefit of IMM compared to DEF was maintained, increased, or reduced, Cox models were used to estimate and compare hazard ratios (HR, IMM:DEF), for the primary endpoint and its components from randomization through 31Dec2015 (Pre 2016) with the period 1Jan2016 through 31Dec2021 (Post 2016). HRs for all follow-up, randomization through 31Dec2021, were also estimated. Results Pre 2016, median CD4 was 648 cells/μL in IMM and 460 cells/μL in DEF at ART initiation, a difference of 188 cells/μL (95% CI: 180-197); at the end of 2015, 98.9% of IMM and 84.8% of DEF were prescribed ART. The percentage of follow-up time spent on ART pre 2016 was 94.5% for IMM and 35.5% for DEF; and the average difference in CD4 count was 199 cells/μL. This contrasts with post 2016 during which the percentage of follow-up time on ART was 99.5% for IMM and 95.6% for DEF; and the average difference in CD4 was 155 cells/mL (Figure 1). During both time periods, initiation of ART led to rapid declines in HIV RNA to ≤ 200 copies/mL. For the primary endpoint and each component, the benefit of IMM compared to DEF in Post 2016 was reduced compared to Pre 2016 (Figure 2). Overall follow-up, from randomization to 2021 (median 9.3 years), the HR for the primary endpoint was 0.61 (95%CI: 0.49, 0.76; p< 0.001). Conclusion Among people with CD4 > 500, the excess risk of AIDS and SNA conditions associated with delaying ART initiation is substantially diminished soon after ART is initiated, but persistent excess risk remains. The results reinforce the importance of early diagnosis of HIV and prompt initiation of ART. Disclosures Gail Matthews, MBChB, PhD, Abbvie Inc: Grant/Research Support|Astra Zeneca: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support.

BACKGROUND: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment.OBJECTIVE: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high.DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978).SETTING: Multicenter trial.PATIENTS: Hospitalized patients with COVID-19 without end-organ failure.INTERVENTION: Bamlanivimab (7000 mg) or placebo.MEASUREMENTS: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections).RESULTS: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal P for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (LIMITATION: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed.CONCLUSION: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting.PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Background/aims Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public–private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. Methods Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19. Results As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites. Conclusion Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak.

The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus.

BackgroundUnderstanding the genetic interplay between human hosts and infectious pathogens is crucial for how we interpret virulence factors. Here, we tested for associations between HIV and host genetics, and interactive genetic effects on viral load (VL) in HIV-positive antiretroviral treatment-naive clinical trial participants.MethodsHIV genomes were sequenced and the encoded amino acid (AA) variants were associated with VL, human single nucleotide polymorphisms (SNPs), and imputed HLA alleles using generalized linear models with Bonferroni correction.ResultsHuman (388 501 SNPs) and HIV (3010 variants) genetic data were available for 2122 persons. Four HIV variants were associated with VL (P ConclusionsOur results show the importance of immunotype specificity on viral antigenic determinants, and the identified genetic interplay emphasizes that viral and human genetics should be studied in the context of each other.Clinical Trials Registration: NCT00867048.

BACKGROUND: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.METHODS: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.RESULTS: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).CONCLUSIONS: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).

OBJECTIVES: The Strategic Timing of AntiRetroviral Treatment (START) and Strategies for Management of Antiretroviral Therapy (SMART) trials demonstrated that ART can partly reverse clinically defined immune dysfunction induced by HIV replication. As control of HIV replication is influenced by the HLA region, we explored whether HLA alleles independently influence the risk of clinical events in HIV+ individuals. DESIGN: Cohort study. METHODS: In START and SMART participants, associations between imputed HLA alleles and AIDS, infection-related cancer, herpes virus-related AIDS events, chronic inflammation-related conditions and bacterial pneumonia were assessed. Cox regression was used to estimate hazard ratios (HRs) for the risk of events among allele carriers versus non-carriers. Models were adjusted for sex, age, geography, race, time-updated CD4+ T-cell counts and HIV viral load (VL) and stratified by treatment group within trials. HLA class I and II alleles were analyzed separately. The Benjamini-Hochberg procedure was used to limit the false discovery rate to

Background We performed metabolomic profiling to identify metabolites that correlate with disease progression and death. Methods We performed a study of adults hospitalized with Influenza A(H1N1)pdm09. Cases (n = 32) were defined by a composite outcome of death or transfer to the intensive care unit during the 60-day follow-up period. Controls (n = 64) were survivors who did not require transfer to the ICU. Four hundred and eight metabolites from eight families were measured on plasma sample at enrollment using a mass spectrometry based Biocrates platform. Conditional logistic regression was used to summarize the association of the individual metabolites and families with the composite outcome and its major two components. Results The ten metabolites with the strongest association with disease progression belonged to five different metabolite families with sphingolipids being the most common. The acylcarnitines, glycerides, sphingolipids and biogenic metabolite families had the largest odds ratios based on the composite endpoint. The tryptophan odds ratio for the composite is largely associated with death (OR 17.33: 95% CI, 1.60–187.76). Conclusions Individuals that develop disease progression when infected with Influenza H1N1 have a metabolite signature that differs from survivors. Low levels of tryptophan had a strong association with death. Registry ClinicalTrials.gov Identifier: NCT01056185

HIV treatment has been greatly impacted by transmitted resistance to antiretrovirals (ARV). Several studies have documented resistance in naive individuals and estimates of transmitted drug resistance mutations range from

There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRAs) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC. We found that treatment with the LRA panobinostat or a short analytical treatment interruption (ATI), 21 to 59 days, was not sufficient to stimulate an increase in ADCC-competent antibodies, despite viral rebound in all subjects who underwent the short ATI. In contrast, a longer ATI, 2 to 12 months, among subjects enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial robustly boosted HIV-1 gp120-specific Fc receptor-binding antibodies and ADCC against HIV-1-infected cells in vitro . These results show that there is a lag between viral recrudescence and the boosting of ADCC antibodies, which has implications for strategies toward eliminating latently infected cells. IMPORTANCE The “shock and kill” HIV-1 cure strategy aims to reactivate HIV-1 expression in latently infected cells and subsequently eliminate the reactivated cells through immune-mediated killing. Several latency reversing agents (LRAs) have been examined in vivo , but LRAs alone have not been able to achieve HIV-1 remission and prevent viral rebound following analytical treatment interruption (ATI). In this study, we examined whether LRA treatment or ATI can provide sufficient antigenic stimulus to boost HIV-1-specific functional antibodies that can eliminate HIV-1-infected cells. Our study has implications for the antigenic stimulus required for antilatency strategies and/or therapeutic vaccines to boost functional antibodies and assist in eliminating the latent reservoir.

This study retrospectively evaluated specific changes in renal parameters among HIV-infected patients treated with regimens combining tenofovir (TDF) with ritonavir-boosted protease inhibitor (PI/r) compared with non-nucleoside reverse transcriptase inhibitor (NNRTI), with non-TDF regimens, and with those on no treatment before or during the study period. Patients in the treatment groups were included if they received the same regimen continuously for at least 12 months at our medical center during 2001 to 2008. Changes from baseline creatinine clearance and glomerular filtration rate were assessed at 6 and 12 months. A total of 625 patients met our criteria: 186 on TDF+PI/r, 182 on TDF+NNRTI, 151 on non-TDF antiretroviral regimens, and 106 on no treatment. Our patients were predominantly African-American men. Declines in creatinine clearance and glomerular filtration rate were not significantly different for PI/r versus NNRTI and for any TDF versus non-TDF treatment groups at 6 or 12 months. However, there was a significant decline in creatinine clearance for the treatment when compared with no treatment groups at 12 months (p=0.008) by a multivariate general linear model adjusted for covariates. In this study, no significant differences was found in nephrotoxicity among patients receiving TDF+PI/r compared with those on TDF+NNRTI and among those receiving TDF versus non-TDF regimens for 6 and 12 months. Key words: Tenofovir, ritonavir, nephrotoxicity, renal toxicity, creatinine, creatinine clearance, glomerular filtration rate.

(See the Editorial Commentary by Lautenbach on pages 1266–9.) Escherichia coli causes diverse extraintestinal infections, including urinary tract infection, bacteremia, and meningitis, resulting in considerable morbidity, mortality, and increased costs [1]. Management of such infections is complicated by the rising prevalence of resistance to preferred antimicrobial agents such as trimethoprim-sulfamethoxazole (TMP-SMZ), fluoroquinolones (FQs), and extended-spectrum cephalosporins [1–4]. Contributing to this problem is E. coli sequence type 131 (ST131), a newly emerged, disseminated lineage of multidrug-resistant E. coli [2, 5–9]. In recent surveys ST131 has accounted for up to 10%–27% of the total clinical E. coli population in various locales, and for up to 52%–67% of all extended-spectrum β-lactamase (ESBL)–producing or FQ-resistant (FQ-R) E. coli [2, 10–12]. The Department of Veterans Affairs (VA) operates the largest integrated healthcare system in the United States. [13]. Escherichia coli infections, especially urinary tract infections, are quite common among veterans [14]. Based on associations of ST131 with older age and health care contact [15], and the high prevalence of these characteristics among veterans, we hypothesized that ST131 may contribute importantly to antimicrobial resistance in E. coli among veterans. Accordingly, we assessed the prevalence, geographic distribution, and contribution to antimicrobial resistance of E. coli ST131 among US veterans during 2010–2011 at multiple VA medical centers (VAMCs) across the United States, and explored associations of ST131 with source and fitness-promoting bacterial traits.

Candidemia is an important cause of morbidity and mortality. As statins interfere with yeast membrane synthesis, we assessed whether use of statins during candidemia may cause differences in clinical outcomes. A retrospective review of 124 candidemia episodes during 2003-2008 in which all-cause and attributable mortality, length of stay and level of care were compared for patients who received and those who did not receive statins. A total of 124 candidemia events were observed involving 14 patients on statins and 110 without statins. Overall mortality in candidemia cases was 46%, but only 2% was attributed to candidemia. No differences were observed in clinical outcomes for the two groups of patients. During the last 2-year period of our study, there were higher rates of candidemia caused by non-C. albicans Candida spp., particularly those due to C. glabrata and C. parapsilosis. In conclusion, statin use during candidemia did not alter mortality, length of stay, or intensive care requirement of our patients, despite higher rates of non-C. albicans Candida species isolated during the last 2 years of our study.

Among patients infected with human immunodeficiency virus (HIV), those with HIV-1 RNA

Veterans Health Administration changed its HIV testing policy to remove requirements for written informed consent with pretest/posttest counseling and to make testing part of routine care in August 2009. HIV testing percentages were compared for 1-year periods before and after this change at our medical center located in Washington, DC, the city with the highest US HIV prevalence. After this policy change, HIV screening rose from 5.5% to 10.3% of persons in care with the majority of testing in outpatient settings and the greatest increase among veterans aged 61-70. Broadening of HIV testing has significance for HIV detection and prevention.

Using real-time technology, we reliably identified chronic hepatitis C virus (HCV) infection and quantified virus from reflex samples originally submitted for serologic testing. There was no need to process specimens obtained directly for quantitation separately. Whether the initial source is a reflex sample or one obtained directly, a repeat HCV RNA test is needed before starting treatment.

There have been few reports evaluating the prevalence of genotypic mutations and antiretroviral resistance among chronic HIV-infected Veterans within the United States. This retrospective cross-sectional study characterizes the rates and changes in HIV genotypic mutations and antiretroviral resistance among viremic patients from 2001 to 2006 at the VA Medical Center located in Washington, DC. The District of Columbia is the metropolitan area with the highest HIV prevalence within the United States. De-identified, linked HIV RNA, genotypic reverse transcriptase (RT) and protease (Pr) mutations and antiretroviral resistance results were assessed for changes during the 6-year period. Aggregated clinic and antiretroviral utilization, and HIV acquisition risk data were evaluated for patients in care during this time. Among 990 viremic samples, the rate of any detected RT or Pr mutation fell from 100% in 2001 to 95% in 2006. This was primarily attributable to the 15% - 20% decrease seen for RT gene mutations against nucleoside/nucleotide class and non-nucleoside class during this period. Resistance to didanosine, stavudine, zidovudine, nevirapine and efavirenz decreased, and tenofovir resistance increased. Despite stable rates of Pr gene mutations, atazanavir resistance increased by 22% from 2003 to 2006. Some but not all changes in genotypic mutations and resistance patterns reflected our patients’ antiretroviral drug utilization. As sexual contacts (77%) and injection drug use (22%) were the leading acquisition risks disclosed by our HIV-infected patients, the high prevalence and changing patterns of HIV genotypic mutations and drug resistance among these patients have had pivotal impacts not only on HIV treatment but potential transmission into our community.

Objectives. We assessed rates of HIV testing based on targeting patients with identified risk factors at the Veterans Affairs Medical Center in Washington, DC (VAMC-DC), where written informed consent along with pretest and posttest counseling had, until recently, been required by federal law. Methods. A cumulative retrospective review of the period 2000 through 2007 was conducted to assess the number of patients who were provided medical care at VAMC-DC, tested for HIV, and underwent confirmatory testing. Data on demographic characteristics and risks for HIV acquisition were also collected. Results. At VAMC-DC, 3.8% to 4.9% (mean = 4.25%) of patients in care without known HIV infection underwent HIV screening annually. On average, HIV was confirmed at a yearly rate of 3.4% among those tested. During the study period, HIV prevalence ranged from 2.1% to 2.5%. Among patients receiving HIV care, 41.5% disclosed no risk factors for HIV acquisition. Conclusions. Given that the HIV prevalence observed in this study was above 2% and that 41.5% of patients in care did not disclose any acquisition risks, targeted HIV screening has not been sufficient. HIV testing must be broadened and offered as part of routine medical care.

Author(s): Goetz, Matthew Bidwell; Hoang, Tuyen; Kan, Virginia L; Rimland, David; Rodriguez-Barradas, Maria C; Asch, Steven M | Abstract: ObjectiveTo determine predictors and variations in the rate of newly diagnosed HIV infection among persons who underwent routine (ie, non-risk based) rather than risk-based HIV testing in Veterans Health Administration (VHA) facilities.MethodsRetrospective observational study of the HIV infection new rates during the period when VHA policy called for routine (2009-2012) versus risk-based (2006-2009) HIV testing. Source data for testing results at 18 VHA facilities were obtained from the VHA National Corporate Data Warehouse.ResultsNew HIV diagnoses were established in 0.14% (95% confidence interval (CI): 0.12 to 0.46) of the 210,957 patients tested in the routine testing period versus 0.46% (95% CI: 0.42 to 1.29) of the 89,652 patients tested in the risk-based testing period. Among persons aged 65-74 years and 75 years or older, the new diagnosis rates were 0.07% (95% CI: 0.04 to 0.09) and 0.02% (95% CI: 0.00 to 0.03), respectively, and thus less than the generally accepted cost-effective threshold of 0.10%. Among African Americans, the upper bound of the 95% CI of the crude rate of new diagnoses during the routine-testing period was greater than 0.1% across all age strata. When assessed by year of testing, the adjusted rates of new diagnoses fell from 0.20% in 2010 to 0.10% in 2012.ConclusionsRoutine HIV testing is cost-effective among persons younger than 65 years. Among older patients, risk-based testing may be a more efficient and cost-effective approach. This will be increasingly relevant if rates of new HIV diagnoses in persons undergoing routine testing continue to decrease.

The TruGene human immunodeficiency virus type 1 (HIV-1) genotyping kit/OpenGene DNA sequencing system (Bayer HealthCare, Tarrytown, NY) reliably produced clinically acceptable resistance profiles for reverse transcriptase and protease inhibitors on patient samples diluted to ∼100 copies/ml following extraction with the QIAamp viral RNA minikit (QIAGEN Inc., Valencia, CA). One modification of the standard protocol was made to guarantee PCR amplification: a centrifugation step to concentrate virus was added before RNA extraction. For genotypic antiretroviral resistance testing, no significant differences in the identification and sensitivity of detection for codon mutations, base mutations, and multibase sites were found between the original and diluted samples.

The Abbott RealTime HCV Genotype II RUO (research use only) assay was evaluated using the automated Abbott RealTime m 2000 system. Concordance was 98% (81/83 samples) with samples previously typed by the Versant HCV Genotype 2.0 RUO system with manual extraction. The total assay time was reduced from 10.5 to 6.0 h and hands-on time from 13 to 4 min/patient sample.

Background After a case of rabies, healthcare workers (HCWs) had fear of contagion from the infected patient. Although transmission of rabies to HCWs has never been documented, high-risk exposures theoretically include direct contact of broken skin and/or mucosa with saliva, tears, oropharyngeal secretions, cerebrospinal fluid, and neural tissue. Urine/kidney exposure posed a concern, as our patient's renal transplant was identified as the infection source. Methods Our risk assessment included (1) identification of exposed HCWs; (2) notification of HCWs; (3) risk assessment using a tool from the local health department; (4) supplemental screening for urine/kidney exposure; and (5) postexposure prophylaxis (PEP) when indicated. Results A total of 222 HCWs including diverse hospital staff and medical trainees from university affiliates were evaluated. Risk screening was initiated within 2 hours of rabies confirmation, and 95% of HCWs were assessed within the first 8 days. There were 8 high-risk exposures related to broken skin contact or mucosal splash with the patient's secretions, and 1 person without high-risk contact sought and received PEP outside our hospital. Nine HCWs (4%) received PEP with good tolerance. Due to fear of rabies transmission, additional HCWs without direct patient contact required counseling. There have been no secondary cases after our sentinel rabies patient. Conclusions Rabies exposure represents a major concern for HCWs and requires rapid, comprehensive risk screening and counseling of staff and timely PEP. Given the lack of human-to-human rabies transmission from our own experience and the literature, a conservative approach seems appropriate for providing PEP to HCWs.

An algorithm was developed that identifies patients with new diagnoses of HIV infection by the use of electronic health records. It was based on the sequence of HIV diagnostic tests, entry of ICD-9-CM diagnostic codes, and measurement of HIV-1 plasma RNA levels in persons undergoing HIV testing from 2006 to 2012 at four large urban Veterans Health Administration (VHA) facilities. Source data were obtained from the VHA National Corporate Data Warehouse. Chart review was done by a single trained abstractor to validate site-level data regarding new diagnoses. We identified 1,153 patients as having a positive HIV diagnostic test within the VHA. Of these, 57% were determined to have prior knowledge of their HIV status from testing at non-VHA facilities. An algorithm based on the sequence and results of available laboratory tests and ICD-9-CM entries identified new HIV diagnoses with a sensitivity of 83%, specificity of 86%, positive predictive value of 85%, and negative predictive value of 90%. There were no meaningful demographic or clinical differences between newly diagnosed patients who were correctly or incorrectly classified by the algorithm. We have validated a method to identify cases of new diagnosis of HIV infection in large administrative datasets. This method, which has a sensitivity of 83%, specificity of 86%, positive predictive value of 85%, and negative predictive value of 90% can be used in analyses of the epidemiology of newly diagnosed HIV infection. © Copyright 2014, Mary Ann Liebert, Inc. 2014.

The statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, act to regulate the biosynthesis of cholesterol. Statins also deplete nonsterol cholesterol precursors, the isoprenoids, which are necessary for prenylation of critical membrane proteins that regulate cellular communication, including the inflammatory response. In a retrospective review of 388 bacteremic infections due to aerobic gram-negative bacilli and Staphylococcus aureus, there was a significant reduction in both overall (6% vs. 28%; P=.002) and attributable (3% vs. 20%; P=.010) mortality among patients taking statins compared with patients not taking statins. This reduction in mortality persisted in a multivariate analysis (odds ratio, 7.6; 95% confidence interval, 1.01-57.5). Among the statin group, diabetes, hypertension, and coronary artery disease were more prevalent (P

Aspergillosis comprises a variety of manifestations of infection. These guidelines are directed to 3 principal entities: invasive aspergillosis, involving several organ systems (particularly pulmonary disease); pulmonary aspergilloma; and allergic bronchopulmonary aspergillosis. The recommendations are distilled in this summary, but the reader is encouraged to review the more extensive discussions in subsequent sections, which show the strength of the recommendations and the quality of the evidence, and the original publications cited in detail. Invasive aspergillosis. Because it is highly lethal in the immunocompromised host, even in the face of therapy, work-up must be prompt and aggressive, and therapy may need to be initiated upon suspicion of the diagnosis, without definitive proof (BIII). Intravenous therapy should be used initially in rapidly progressing disease (BIII). The largest therapeutic experience is with amphotericin B deoxycholate, which should be given at maximum tolerated doses (e.g., 1-1.5 mg/kg/d) and should be continued, despite modest increases in serum creatinine levels (BIII). Lipid formulations of amphotericin are indicated for the patient who has impaired renal function or who develops nephrotoxicity while receiving deoxycholate amphotericin (AII). Oral itraconazole is an alternative for patients who can take oral medication, are likely to be adherent, can be demonstrated (by serum level monitoring) to absorb the drug, and lack the potential for interaction with other drugs (BII). Oral itraconazole is attractive for continuing therapy in the patient who responds to initial iv therapy (CIII). Therapy should be prolonged beyond resolution of disease and reversible underlying predispositions (BIII). Adjunctive therapy (particularly surgery and combination chemotherapy, also immunotherapy), may be useful in certain situations (CIII). Aspergilloma. The optimal treatment strategy for aspergilloma is unknown. Therapy is predominantly directed at preventing life-threatening hemoptysis. Surgical removal of aspergilloma is definitive treatment, but because of significant morbidity and mortality it should be reserved for high-risk patients such as those with episodes of life-threatening hemoptysis, and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). Surgical candidates would need to have adequate pulmonary function to undergo the operation. Bronchial artery embolization rarely produces a permanent success, but may be useful as a temporizing procedure in patients with life-threatening hemoptysis. Endobronchial and intracavitary instillation of antifungals or oral itraconazole may be useful for this condition. Since the majority of aspergillomas do not cause life-threatening hemoptysis, the morbidity and cost of treatment must be weighed against the clinical benefit. Allergic bronchopulmonary aspergillosis (APBA). Although no well-designed studies have been carried out, the available data support the use of corticosteroids for acute exacerbations of ABPA (AII). Neither the optimal corticosteroid dose nor the duration of therapy has been standardized, but limited data suggest the starting dose should be approximately 0.5 mg/kg/d of prednisone. The decision to taper corticosteroids should be made on an individual basis, depending on the clinical course (BIII). The available data suggest that clinical symptoms alone are inadequate to make such decisions, since significant lung damage may occur in asymptomatic patients. Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids should be used (BII). Multiple asthmatic exacerbations in a patient with ABPA suggest that chronic corticosteroid therapy should be used (BIII). Itraconazole appears useful as a corticosteroid sparing agent (BII). (ABSTRACT TRUNCATED)

A retrospective analysis of 13,946 Staphylococcus aureus isolates revealed a stable incidence of isolates that were resistant to both clindamycin and erythromycin, but a significantly increasing incidence of isolates that were susceptible to clindamycin and resistant to erythromycin during 1991-1995, 1996-2000, and 2001-2005. The use of macrolides and clindamycin also increased during 1996-2005. The incidence of S. aureus isolates with inducible clindamycin resistance increased steadily and significantly during the period from August 2004 through December 2005.

Although adverse events in HIV patients taking tenofovir are relatively rare, postmarketing reports of nephrotoxicity have alerted physicians to other potentially serious outcomes. We present a series of 40 patients who developed hypokalemia associated with tenofovir. Identified risk factors included concomitant ritonavir or didanosine use, a lower weight and longer duration of tenofovir use. Recovery or improvement was seen in the majority of patients (66%) after the discontinuation of tenofovir; however, four deaths occurred. The associated consequences of tenofovir-related hypokalemia may be profound and life-threatening.

Background: The most recent guidance statement from The American College of Physicians recommends that clinicians adopt human immunodeficiency virus screening as part of routine medical care. Inpatient HIV testing at the Vetarns Affairs Medical Center in Washington, DC has been predominantly targeted at patients with disclosed risk factors. Method: We implemented the first voluntary inpatient HIV testing program within a Veterans Affairs hospital using the OraQuick Advance Rapid HIV-1/2 Antibody Test on both oral secretion and whole blood samples. Results: During a 17 month period we offered 3,467 inpatients testing and performed 824 rapid HIV tests. All reactive results were Western blot confirmed. Ten patients (1.2%) had reactive test results. Seven (0.8%) represented new HIV diagnoses, and three had been previously diagnosed outside the VA. Five patients had AIDS at the time of testing by CD4 criteria. Nine patients were linked to care and six patients were started on antiretroviral therapy. There were no false-positive results. Conclusion: We have demonstrated how expanding HIV-POC testing among hospitalized patients can enhance patients' acceptance for screening, can detect HIV-infected individuals who might not have been tested with conventional targeted testing, and can improve linkage to care for those with HIV infection.

The only US licensed vaccine with established efficacy against smallpox, Dryvax, is contraindicated for HIV patients. Detectable smallpox-neutralizing antibodies are still present among US adults. This study compared vaccinia-neutralizing antibody titers between 20 HIV-infected and 20 uninfected veterans matched for age and military entry. Vaccinia-neutralizing antibodies were detected in 95% HIV-infected and 100% uninfected veterans; 40% HIV-infected and 70% uninfected adults had protective titers. Therefore, after robust vaccination, neutralizing antibodies are maintained for prolonged times despite CD4 cell depletion.

The binding of Aspergillus fumigatus conidia to human monocytes is mediated by a barley beta-glucan-inhibitable receptor. The simplest linkages in this glucan are present in the disaccharides laminaribiose (beta 1,3) and cellobiose (beta 1,4). Although laminaribiose gave strong inhibition of conidial binding to monocytes, cellobiose and oligosaccharides with beta 1,4-linked glucose residues were more potent as specific inhibitors of this binding over similar concentrations. Increasing the number of beta 1,4-linked glucose residues led to greater inhibition of conidial binding by human monocytes.

Background HIV-1 RNA and CD4 cell counts are important parameters for HIV care. The objective of this study was to assess the overall trends in HIV-1 viral load and CD4 cell counts within our clinic. Methods Patients with at least one of each test performed by the Infectious Diseases Laboratory from 1999 through 2011 were included in this analysis. By adapting a novel statistical model, log10 HIV-1 RNA means were estimated by month, and log10-transformed HIV-1 RNA means were estimated by calendar year. Geometric means were calculated for CD4 cell counts by month and calendar year. Log10 HIV-1 RNA and CD4 cell count monthly means were also examined with polynomial regression. Results There were 1,814 individuals with approximately 25,000 paired tests over the 13-year observation period. Based on each patient's final value of the year, the percentage of patients with viral loads below the lower limit of quantitation rose from 29% in 1999 to 72% in 2011, while the percentage with CD4 counts

The susceptibility of genetically defined Candida glabrata strains to killing by H2O2 and neutrophils was assessed. Fluconazole-susceptible L5L and L5D strains demonstrated survival rates higher than those of two fluconazole-resistant strains lacking the ERG11 gene coding for 14 alpha-demethylase. Fluconazole resistance can occur by mechanisms which increase fungal susceptibility to oxidative killing by H2O2 and neutrophils.

A PCR assay was developed for the diagnosis of candidemia. Primers were selected to amplify a 158-bp segment from the Candida actin gene that was detected by hybridization with a 32P-labeled oligomer probe. The lower limit of detection was DNA extracted from 10 Candida yeasts/sample, or 25 fg of purified Candida albicans DNA. This PCR was specific for medically important Candida species. Circulating Candida DNA was detected by this PCR from plasma of mice with induced candidemia and from sera in 11 (79%) of 14 patients with blood cultures positive for Candida species. This PCR may offer a sensitive method for diagnosis of candidemia.