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Background . Up to 20% of people with HIV (PWH) who undergo virologically suppressed antiretroviral therapy (ART) fail to experience complete immune restoration. We recently reported that plasma anti-CD4 IgG (antiCD4IgG) autoantibodies from immune non-responders specifically deplete CD4 + T cells via antibody-dependent cytotoxicity. However, the mechanism of antiCD4IgG production remains unclear. Methods . Blood samples were collected from 16 healthy individuals and 25 PWH on suppressive ART. IgG subclass, plasma lipopolysaccharide (LPS), and antiCD4IgG levels were measured by ELISA. Gene profiles in B cells were analyzed by microarray and quantitative PCR. Furthermore, a patient-derived antiCD4IgG–producing B cell line was generated and stimulated with LPS in vitro. B cell IgG class switch recombination (CSR) was evaluated in response to LPS in splenic B cells from C57/B6 mice in vitro. Results . Increased plasma anti-CD4 IgGs in PWH were predominantly IgG1 and associated with increased plasma LPS levels as well as B cell expression of TLR2, TLR4, and MyD88 mRNA in vivo. Furthermore, LPS stimulation induced antiCD4IgG production in the antiCD4IgG B cell line in vitro. Finally, LPS promoted CSR in vitro. Conclusion . Our findings suggest that persistent LPS translocation may promote anti-CD4 autoreactive B cell activation and antiCD4IgG production in PWH on ART, which may contribute to gradual CD4 + T cell depletion. This study suggests that reversing a compromised mucosal barrier could improve ART outcomes in PWH who fail to experience complete immune restoration.

Context Tocilizumab (TCZ), an interleukin-6 (IL-6) receptor antagonist, has been approved for use in rheumatoid arthritis and cytokine storm syndrome (CSS) associated with chimeric antigen receptor T cells treatment. Although TCZ is currently utilized in the treatment of critically ill coronavirus 2019 (COVID-19) patients, data on survival impact is minimal. Objectives To assess the mortality rate of patients presenting with COVID-19 who received TCZ for suspected CSS. Methods This retrospective cohort study was conducted at Henry Ford Health System between March 10, 2020 and May 18, 2020. Data collection began in May 2020 and was completed in June 2020. Patients included in the study required hospital admission and had positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction on nasopharyngeal swab. Eligibility criteria to receive TCZ, per hospital protocol, included any of the following: persistent fever, defined as 38.0 °C for at least 6 hours; a diagnosis of the acute respiratory distress syndrome (ARDS); serum ferritin ≥1,000 (ng/mL) or doubling within 24 hours; D-Dimer ≥ 5 (mg/L); serum lactate dehydrogenase ≥500 (IU/L); or interlukin-6 level ≥5 times the upper limit of normal. Dosing was initially determined by weight, then changed to a fixed 400 mg per hospital protocol. A comparator cohort was created from patients with COVID-19 and ARDS who did not receive TCZ. Patient survival was analyzed using the Kaplan–Meier method and compared by log rank test. A multivariable cox regression was applied to evaluate the association between TCZ and mortality. Results One hundred and thirty patients were evaluated in the study, 54 (41.5%) of whom received TCZ. Patients who received TCZ were younger (mean age, 63.8 vs. 69.4 years; p=0.0083) and had higher body mass indices (mean, 33.9 vs. 30.4; p=0.005). Of the comorbid conditions evaluated, heart disease was more common in the comparator group than the TCZ group (27 patients [35.5%] vs. 10 patients [18.5%]; p=0.034). A Kaplan–Meier survival curve demonstrated no difference in survival between TCZ and comparator patients (log rank p=0.495). In the multivariable Cox regression model for mortality at 30 days, treatment with TCZ was not associated with decreased mortality (hazard ratio, 1.1; 95% confidence interval, 0.53–2.3; p=0.77). Lower mean C-reactive protein (CRP) levels were demonstrated within 48 hours of disposition in the TCZ group (mean TCZ, 4.9 vs. mean comparator, 13.0; p= Conclusions In this cohort study, no difference in survival was observed in critically ill patients treated with TCZ.

Significance The United States is in an acceleration phase of the COVID-19 pandemic. Currently there is no known effective therapy or vaccine for treatment of SARS-CoV-2, highlighting urgency around identifying effective therapies. Objective The purpose of this study was to evaluate the role of hydroxychloroquine therapy alone and in combination with azithromycin in hospitalized patients positive for COVID-19. Design Multi-center retrospective observational study. Setting The Henry Ford Health System (HFHS) in Southeast Michigan: large six hospital integrated health system; the largest of hospitals is an 802-bed quaternary academic teaching hospital in urban Detroit, Michigan. Participants Consecutive patients hospitalized with a COVID-related admission in the health system from March 10, 2020 to May 2, 2020 were included. Only the first admission was included for patients with multiple admissions. All patients evaluated were 18 years of age and older and were treated as inpatients for at least 48 h unless expired within 24 h. Exposure Receipt of hydroxychloroquine alone, hydroxychloroquine in combination with azithromycin, azithromycin alone, or neither. Main outcome The primary outcome was in-hospital mortality. Results Of 2,541 patients, with a median total hospitalization time of 6 days (IQR: 4–10 days), median age was 64 years (IQR:53–76 years), 51% male, 56% African American, with median time to follow-up of 28.5 days (IQR:3–53). Overall in-hospital mortality was 18.1% (95% CI:16.6%–19.7%); by treatment: hydroxychloroquine + azithromycin, 157/783 (20.1% [95% CI: 17.3%–23.0%]), hydroxychloroquine alone, 162/1202 (13.5% [95% CI: 11.6%–15.5%]), azithromycin alone, 33/147 (22.4% [95% CI: 16.0%–30.1%]), and neither drug, 108/409 (26.4% [95% CI: 22.2%–31.0%]). Primary cause of mortality was respiratory failure (88%); no patient had documented torsades de pointes. From Cox regression modeling, predictors of mortality were age > 65 years (HR:2.6 [95% CI:1.9–3.3]), white race (HR:1.7 [95% CI:1.4–2.1]), CKD (HR:1.7 [95%CI:1.4–2.1]), reduced O2 saturation level on admission (HR:1.5 [95%CI:1.1–2.1]), and ventilator use during admission (HR: 2.2 [95%CI:1.4–3.3]). Hydroxychloroquine provided a 66% hazard ratio reduction, and hydroxychloroquine + azithromycin 71% compared to neither treatment (p Conclusions and relevance In this multi-hospital assessment, when controlling for COVID-19 risk factors, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality. Prospective trials are needed to examine this impact.

The surge of coronavirus disease 2019 (COVID-19) hospitalizations at our 877-bed quaternary care hospital in Detroit led to an emergent demand for Infectious Diseases (ID) consultations. The traditional 1-on-1 consultation model was untenable. Therefore, we rapidly restructured our ID division to provide effective consultative services. We implemented a novel unit-based group rounds model that focused on delivering key updates to teams and providing unit-wide consultations simultaneously to all team members. Effectiveness of the program was studied using Likert-scale survey data. The survey captured data from the first month of the Detroit COVID-19 pandemic. During this period there were approximately 950 patients hospitalized for treatment of COVID-19. The survey of trainees and faculty reported an overall 95% positive response to delivery of information, new knowledge acquisition, and provider confidence in the care of COVID-19 patients. This showed that the unit-based consult model is a sustainable effort to provide care during epidemics.

Background: Health care workers (HCW) are among the highest risk groups for acquisition of COVID-19 because of occupational exposures. The WHIP COVID-19 Study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) as chemoprophylaxis for SARS-CoV-2 infection in this population. Methods: HCW, first responders, and other occupationally high-risk participants were enrolled in a randomized, placebo-controlled clinical study of HCQ from April to October 2020. The trial compared daily versus weekly HCQ with placebo and with a prospective cohort on HCQ for autoimmune diseases. Participants were followed for 8 weeks. Serology or a positive polymerase chain reaction test was used to determine laboratory confirmed clinical cases. Results: A total of 624 participants were randomized to placebo (n = 200), weekly HCQ (n = 201), daily HCQ (n = 197). For the primary safety end point, 279 (44.7%) participants experienced adverse event (AE) level II or lower (total AEs n = 589), similar rates in all randomized groups (P = .188) with no hospitalizations or interventions required. Only 4 laboratory confirmed COVID-19 cases occurred, with 2 in the placebo arm and one in each HCQ randomized arm. Conclusions: This randomized placebo-controlled trial was able to demonstrate the safety of HCQ outpatient chemoprophylaxis in high-risk groups against COVID-19. Future studies of chemoprophylaxis for SARS-CoV-2 are needed as the epidemic continues worldwide.

Daily adherence to lifelong antiretroviral therapy (ART) is required to achieve long term treatment success. However, patient preferences for ART tablet size have not been well studied. Our study assessed factors associated with the ease of swallowing (EoS) and tolerability of two placebo tablets representing and matching B/F/TAF (BPT) and DTG/ABC/3TC (DPT). Fifty ART-naïve patients were randomized into a two-period cross-over study. Likert scale (1-5) questionnaires were administered to assess patient factors influencing the ease of swallowing, adherence, home medications, medication preferences and perceptions. Comparisons were done using Student

Supplemental Digital Content is available in the text, Objective: Examine the effect of a universal facemask policy for healthcare workers (HCW) and incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity. Methods: Daily number of symptomatic HCW tested, SARS-CoV-2 positivity rates, and HCW job-descriptions were collected pre and post Universal HCW facemask policy (March 26, 2020). Multiple change point regression was used to model positive-test-rate data. SARS-CoV-2 testing and positivity rates were compared for pre-intervention, transition, post-intervention, and follow-up periods. Results: Between March 12 and August 10, 2020, 19.2% of HCW were symptomatic for COVID-19 and underwent SARS-CoV-2 testing. A single change point was identified ∼March 28–30 (95% probability). Before the change point, the odds of a tested HCW having a positive result doubled every 4.5 to 7.5 days. Post-change-point, the odds of a tested HCW having a positive result halved every 10.5 to 13.5 days. Conclusions: Universal facemasks were associated with reducing HCW's risk of acquiring COVID-19.

Approximately 9 months of the severe acute respiratory syndrome coronavius-2 (SARS-CoV-2 [COVID-19]) spreading across the globe has led to widespread COVID-19 acute hospitalizations and death. The rapidity and highly communicable nature of the SARS-CoV-2 outbreak has hampered the design and execution of definitive randomized, controlled trials of therapy outside of the clinic or hospital. In the absence of clinical trial results, physicians must use what has been learned about the pathophysiology of SARS-CoV-2 infection in determining early outpatient treatment of the illness with the aim of preventing hospitalization or death. This article outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic therapy, and 5) administration of oxygen, monitoring, and telemedicine. Future randomized trials testing the principles and agents discussed will undoubtedly refine and clarify their individual roles; however, we emphasize the immediate need for management guidance in the setting of widespread hospital resource consumption, morbidity, and mortality.

Subclinical cytomegalovirus (CMV) viremia has been associated with other infections, prolonged hospitalization, and mortality in select immunosuppressed populations. We examined the incidence and outcomes of subclinical CMV viremia in hospitalized patients with systemic autoimmune diseases (AD) [systemic lupus erythematosus (SLE) or anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)] using a highly sensitive CMV assay.Prospectively collected samples were obtained from AD hospitalized patients at study entry with a second sample collected 1 week later or at hospital discharge. Controls included age- and gender- matched inpatients without AD and outpatients with AD. All samples were tested in batch using the Abbott RealTime CMV for investigational use assay (RT assay), with a LLOD (LLOQ) at 21 IU/mL (32 IU/mL).Twenty-three inpatients (10 SLE, 8 AAV, 5 controls), and 31 outpatient controls were recruited. Subclinical CMV viremia was found in 61% (11/18) of inpatient AD subjects, 3% (1/31) of outpatient AD subjects, and in none of the five inpatient controls (p 0.001). CMV viremia was associated with increased median length of ICU stay (13 vs. 4 days, p = 0.033), hospital stay (17 vs. 9 days, p = 0.014) and increased nosocomial infections (7 vs. 1, p = 0.007). CMV viremia was not associated with overall severity of illness nor with disease-specific activity or damage.Over one-half of hospitalized AD patients in our cohort had detectable CMV viremia, which was associated with increased length of hospital stay and nosocomial infections. These data suggest that further study of the immunomodulatory effects of subclinical CMV viremia in AD is warranted.

ObjectiveTo determine if hydroxychloroquine (HCQ) reduces the incidence of new illness, hospitalization or death among outpatients at risk for or infected with SARS-CoV-2 (COVID-19).DesignSystematic review and meta-analysis of randomized clinical trials.Data sourcesSearch of MEDLINE, EMBASE, PubMed, medRxiv, PROSPERO, and the Cochrane Central Register of Controlled Trials. Also review of reference lists from recent meta-analyses.Study selectionRandomized clinical trials in which participants were treated with HCQ or placebo/standard-of-care for pre-exposure prophylaxis, post-exposure prophylaxis, or outpatient therapy for COVID-19.MethodsTwo investigators independently extracted data on trial design and outcomes. Medication side effects and adverse reactions were also assessed. The primary outcome was COVID-19 hospitalization or death. When unavailable, new COVID-19 infection was used. We calculated random effects meta-analysis according to the method of DerSimonian and Laird. Heterogeneity between the studies was evaluated by calculation of Cochran Q and I2parameters. An Egger funnel plot was drawn to investigate publication bias. We also calculated the fixed effects meta-analysis summary of the five studies. All calculations were done in Excel, and results were considered to be statistically significant at a two-sided threshold of P=.05.ResultsFive randomized controlled clinical trials enrolling 5,577 patients were included. HCQ was associated with a 24% reduction in COVID-19 infection, hospitalization or death, P=.025 (RR, 0.76 [95% CI, 0.59 to 0.97]). No serious adverse cardiac events were reported. The most common side effects were gastrointestinal.ConclusionHydroxychloroquine use in outpatients reduces the incidence of the composite outcome of COVID-19 infection, hospitalization, and death. Serious adverse events were not reported and cardiac arrhythmia was rare.Systematic review registrationThis review was not registered.

Introduction: Hydroxychloroquine has been used for rheumatological diseases for many decades and is considered a safe medication. With the COVID-19 outbreak, there has been an increase in reports associating cardiotoxicity with hydroxychloroquine. It is unclear if the cardiotoxic profile of hydroxychloroquine is previously underreported in the literature or is it a manifestation of COVID-19 and therapeutic interventions. This manuscript evaluates the incidence of cardiotoxicity associated with hydroxychloroquine prior to the onset of COVID-19. Methods: PubMED, EMBASE, and Cochrane databases were searched for keywords derived from MeSH terms prior to April 9, 2020. Inclusion eligibility was based on appropriate reporting of cardiac conditions and study design. Results: A total of 69 articles were identified (58 case reports, 11 case series). The majority (84%) of patients were female, with a median age of 49.2 (range 16-92) years. 15 of 185 patients with cardiotoxic events were in the setting of acute intentional overdose. In acute overdose, the median ingestion was 17,857 ± 14,873 mg. 2 of 15 patients died after acute intoxication. In patients with long-term hydroxychloroquine use (10.5 ± 8.9 years), new onset systolic heart failure occurred in 54 of 155 patients (35%) with median cumulative ingestion of 1,493,800 ± 995,517 mg. The majority of patients improved with the withdrawal of hydroxychloroquine and standard therapy. Conclusions: Millions of hydroxychloroquine doses are prescribed annually. Prior to the COVID-19 pandemic, cardiac complications attributed to hydroxychloroquine were uncommon. Further studies are needed to understand the impact of COVID-19 on the cardiovascular system to understand the presence or absence of potential medication interactions with hydroxychloroquine in this new pathophysiological state.

Background COVID-19 disease has spread globally and was declared a pandemic on March 11, 2020, by the World Health Organization. On March 10, the State of Michigan confirmed its first 2 cases of COVID-19, and the number of confirmed cases has reached 47,182 as of May 11, 2020, with 4555 deaths. Setting Currently, little is known if patients living with HIV (PLWH) are at a higher risk of severe COVID-19 or if their antiretrovirals are protective. This study presents epidemiologic and clinical features of COVID-19 infected PLWH in Detroit, Michigan. Methods This is a case series that included 14 PLWH with laboratory-confirmed COVID-19 infection who were evaluated at Henry Ford Hospital in Detroit, Michigan, between March 20, 2020, and April 30, 2020. Results Fourteen PLWH were diagnosed with COVID-19. Twelve patients were men and 2 were women; 13 patients were virally suppressed. Eight patients were hospitalized, and 6 patients were told to self-quarantine at home after their diagnoses. Three patients who were admitted expired during their hospital stay. No patient required bilevel positive airway pressure or nebulizer use in the emergency department, and none developed acute respiratory distress syndrome, pulmonary embolism, deep venous thrombosis, or a cytokine storm while on therapy for COVID-19. Conclusion Although the clinical spectrum of COVID-19 among PLWH cannot be fully ascertained by this report, it adds to the data that suggest that HIV-positive patients with SARS-CoV-2 infection are not at a greater risk of severe disease or death as compared to HIV-negative patients.

Symptomatic cytomegalovirus (CMV) disease has been the standard endpoint for clinical trials in organ transplant recipients. Viral load may be a more relevant endpoint due to low frequency of disease. We performed a meta-analysis and systematic review of the literature. We found several lines of evidence to support the validity of viral load as an appropriate surrogate end-point, including the following: (1) viral loads in CMV disease are significantly greater than in asymptomatic viremia (odds ratio, 9.3 95% confidence interval, 4.6-19.3); (2) kinetics of viral replication are strongly associated with progression to disease; (3) pooled incidence of CMV viremia and disease is significantly lower during prophylaxis compared with the full patient follow-up period (viremia incidence: 3.2% vs 34.3%; P < .001) (disease incidence: 1.1% vs 13.0%; P < .001); (4) treatment of viremia prevented disease; and (5) viral load decline correlated with symptom resolution. Based on the analysis, we conclude that CMV load is an appropriate surrogate endpoint for CMV trials in organ transplant recipients.

The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.

Discrepancies between HIV-1 RNA results assayed by different FDA-approved platforms have been reported. Plasma samples collected from 332 randomly selected clinical trial participants during the second year of antiretroviral treatment were assayed with three FDA-approved platforms: UltraSensitive Roche Amplicor Monitor, v1.5 (Monitor), the Abbott RealTime HIV-1 test on the m2000 system (Abbott), and the Roche TaqMan HIV-1 test, v2.0 (TaqMan). Samples from 61 additional participants with confirmed HIV-1 RNA levels of >50 copies/ml during trial follow-up were also included. Endpoints were HIV-1 RNA quantification of ≤50 copies/ml versus >50 copies/ml at an individual-sample level (primary) and determination of confirmed virologic failure (VF) from longitudinal samples. A total of 389 participants had results obtained from all assays on at least one sample (median = 6). Proportions of results of >50 copies/ml were 19% (Monitor), 22% (TaqMan), and 25% (Abbott). Despite indication of strong agreement (Cohen's kappa, 0.76 to 0.82), Abbott was more likely to detect HIV-1 RNA levels of >50 copies/ml than Monitor (matched-pair odds ratio [mOR] = 4.2; modified Obuchowski P < 0.001) and TaqMan (mOR = 2.1; P < 0.001); TaqMan was more likely than Monitor (mOR = 2.6; P < 0.001). Despite strong agreement in classifying VF across assay comparisons (kappa, 0.75 to 0.92), at a 50-copies/ml threshold, differences in the probability of VF classification (in the same direction as primary) were apparent (all McNemar's P < 0.007). At a 200-copies/ml VF threshold, no differences between assays were apparent (all P > 0.13). Despite strong agreement among assays, significant differences were observed with respect to detecting HIV-1 RNA levels of >50 copies/ml and identifying VF at the 50-copies/ml threshold. This has important implications for the definition of VF in clinical trials and clinical practice.

Peri/post-operative antibiotic prophylaxis (POABP) has become standard practice for preventing surgical site infections (SSI) in head and neck cancer patients undergoing microvascular reconstruction, but few data exist on optimal POABP regimens. Current surgical prophylaxis guideline recommendations fail to account for the complexity of microvascular reconstruction relative to other head and neck procedures, specifically regarding wound classification and antibiotic duration. Selection of POABP spectrum is also controversial, and must balance the choice between too narrow, risking subsequent infection, or too broad, and possible unwanted effects (e.g. antibiotic resistance, Clostridium difficile-associated diarrhea). POABP regimens should retain activity against bacteria expected to colonize the upper respiratory/salivary tracts, which include Gram-positive organisms and facultative anaerobes. However, Gram-negative bacilli also contribute to SSI in this setting. POABP doses should be optimized in order to achieve therapeutic tissue concentrations at the surgical site. Antibiotics targeted towards methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa are not warranted for all patients. Prolonged POABP durations have shown no differences in SSI when compared to short POABP durations, but prolonged durations provide unnecessarily antibiotic exposure and risk for adverse effects. Given the lack of standardization behind antibiotic POABP in this setting and the potential for poor patient outcomes, this practice necessitates an additional focus of surgeons and antimicrobial stewardship programs. The purpose of this review is to provide an overview of POABP evidence and discuss pertinent clinical implications of appropriate use.

Background Human Cytomegalovirus (CMV) infection is prevalent in patients undergoing transplantion (Tx) and carries significant morbidity and mortality. Quantification of CMV viremia has improved with the use of standardized international units and new commercial real time PCR assays. This study compares the current Roche cobas AmpliPrep/cobas TaqMan CMV test (TM assay) and Abbott Molecular RealTime CMV Investigational Use Only assay (ART assay) for quantification of CMV viremia in patients receiving allogeneic hematopoietic stem cell transplants (aHSCT). Methods Prospective CMV positive patients, planned for aHSCT, were consented prior to Tx and followed weekly up 12 weeks post-transplant (PT) and once ~3 months PT. Matched paired plasma samples were processed and analyzed per manufacturer instructions, Henry Ford clinical laboratory processed the samples using the TM assay and the McKinnon Research Laboratory processed the paired samples using the ART assay. Parametric and non-parametric analyses were conducted as appropriate. Results Fourteen patients enrolled, 1 patient withdrew after entering, 1 patient died after 9 weeks PT (primary disease). Patients received peripheral blood stem cells and 84.6% received myeloablative chemotherapy. In paired samples, quantifiable CMV by TM and ART assays was detected in 6 (5 treated) vs. 8 of 13 patients respectively. ART assay detected CMV in all patients with positive paired samples, 1 detected in an unpaired sample and in 2 patients missed by TM assay (P = 0.021). Assays also differed in samples with no detection, detectable and quantifiable CMV viremia, with more frequent detection in the ART assay (P = 0.009). Time to quantifiable viremia PT by TM and ART assays was a median of 5 vs. 3 weeks (P = 0.026). Bland-Altman plot shows higher viremia levels quantified using the ART assay (P = 0.023). After week 4 PT, ART assay results inversely correlated with platelets counts (P = 0.013). CMV viremia tended to persist 1.9 weeks longer using ART vs.. TM assay (P = 0.07). Conclusion CMV viremia was quantified earlier, at higher levels and persisted in patients with aHSCT using the ART assay compared with the TM assay. Further study is warranted to determine clinical impact of ART assay on the management of CMV viremia. Disclosures J. Mckinnon, Abbott Molecular: Speaker’s Bureau, Grant recipient and Speaker honorarium D. Lucic, Abbott Molecular: Employee, Salary

Background Ritonavir-boosted lopinavir (LPV/RTV) alone has been evaluated as simplified maintenance therapy for HIV-1 infection, but there are concerns about greater potential for emergence of protease inhibitor (PI) resistance. The OK04 trial evaluated maintenance therapy with LPV/RTV alone versus standard therapy (ST) with two NRTIs plus LPV/RTV in 205 patients, of whom 15 had virological rebound by week 48 (11 versus 4 patients, respectively). We developed a single genome sequencing (SGS) assay of HIV-1 gag and protease to assess the emergence of low frequency drug-resistant variants during virological rebound. Methods Plasma samples from 15 subjects at virological rebound were analysed by SGS of HIV-1 gag and protease genes. A total of 45 SGS sequences were planned per sample, providing 90% power to detect variants comprising >5% of the virus population. Results Overall, 521 single sequences obtained from 13 patients (range 4–48 sequences/patient) revealed similar frequencies of major protease resistance mutations in samples from the LPV/RTV alone (3/11) and ST (3/4) arms ( P=0.10), with a median number of minor protease resistance mutations of 3.0 versus 3.5, respectively ( P=0.23). Median number of gag PI resistance mutations were similar between the LPV/RTV alone and ST arms at cleavage sites (3.0 versus 2.5; P=0.83), non-cleavage sites (21 versus 16.5; P=0.71) and the transframe protein-p6 pol region cleavage sites (4.0 versus 3.0; P=0.6). Conclusions Although more subjects with simplified maintenance therapy with LPV/RTV alone had virological rebound compared to the ST arm, this was not associated with more frequent emergence of variants encoding PI resistance mutations in gag or protease detected by SGS.

Background Racial and ethnic minorities comprise an increasing proportion of the US population, and are disproportionately affected by HIV. Dyslipidemia is a key comorbidity in HIV due to high prevalence and demonstrated racial disparities in testing and treatment among non-HIV patients. Previous analysis has showed that HIV-positive African American (AA) patients were less likely to have had a lipid profile done and less likely to have been diagnosed with dyslipidemia than other racial groups. Methods Electronic medical records (EMR) identified 1,457 HIV patients from the HIV clinic at Henry Ford Hospital, Detroit, Michigan from March 2013 to November 2015. Race/ethnicity and gender were identified by self-report and then a retrospective EMR review of patients tested for, and documented ICD-9 codes for dyslipidemia was done. Descriptive analyses and group comparisons were performed between AA and other racial/ethnic groups. Results 1,220 HIV patients had lipid levels tested with 25.7% having dyslipidemia after HIV diagnosis. Among those, it was found that lipid abnormalities varied by race; on average, Hispanics, had lower total cholesterol (P = 0.040), AA patients had lower triglycerides (P < 0.001), and White patients had higher triglycerides (P > 0.001). HDL levels were higher in AA patients and lowest in White patients (P < 0.001), while Hispanics had lower LDL values (P-value 0.009). There was no statistically significant (P = 0.519) difference between the lipid lowering drug (LLD) group prescribed by race, and the type of dyslipidemia was the primary predictor of LLD provided to the patients (P < 0.001). Patients prescribed fibrates were statistically more likely to have met their ATP III treatment goals at 1 year as compared with statins, regardless of race (P = 0.005). The odds of meeting treatment goals were 54% (OR 0.46, CI 0.26–0.71) less among AA patients regardless of medication. Conclusion Dyslipidemia is prevalent in our HIV population. Racial differences in testing, lipid abnormalities and treatment outcomes among these vulnerable HIV minorities necessitate further investigation to close the gaps in care and improve our management of dyslipidemia for our HIV patients. Disclosures All authors: No reported disclosures.

Current US guidelines for initial therapy of HIV type-1 (HIV-1) infection recommend daily, lifelong treatment with a combination of three antiretroviral drugs consisting of two nucleoside analogue reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor. Although this approach has been successful in reducing morbidity and mortality from HIV-1 infection, concerns remain about adverse events from chronic drug exposure, the requirement for daily medication adherence, the risk of HIV-1 drug resistance and high treatment costs. The availability of antiretrovirals that are coformulated and dosed once daily have reduced pill burden and have simplified dosing schedules, but have not lowered drug exposure or cost. These limitations have stimulated research into drug-sparing strategies including intermittent therapy and simplified maintenance regimens. Randomized clinical trials have shown greater mortality with intermittent therapy compared with continuous therapy leading to rejection of this strategy. Pilot studies of simplified maintenance therapy with a ritonavir-boosted protease inhibitor alone have shown more promise, although concerns remain. This article reviews progress in the simplification of antiretroviral therapy, recent clinical trial results and prospects for the future.

Background Combination antiretroviral therapy (ART) suppresses HIV-1 replication, but does not restore CD4 T-cell counts in all individuals. To investigate the effects of maraviroc on HIV-1 persistence and the relations between virologic and immunologic parameters in individuals with incomplete CD4 T-cell recovery, we performed a prospective, open-label pilot trial in which maraviroc was added to a suppressive ART regimen for 24 weeks. Design A5256 was a single-arm trial in which individuals on suppressive ART with incomplete CD4 T-cell recovery added maraviroc for 24 weeks. Methods We quantified low-level, residual viremia in plasma and total HIV-1 DNA and 2-long terminal repeat (2-LTR) circles in peripheral blood mononuclear cells before and after maraviroc intensification. We also evaluated markers of CD4 and CD8 T-cell immune activation (%CD38HLA-DR) and apoptosis (%caspase3/Bcl-2). Results No effect of maraviroc was found on the probability of detectable plasma viremia (≥1 copy/ml; n = 31, exact McNemar P = 1.0) or detectable 2-LTR circles (n = 28, P = 0.25) or on total HIV-1 DNA (n = 28, 90% confidence interval -0.1, +0.3 log10 copies/10 CD4 T-cells). Premaraviroc HIV-1 DNA levels were inversely related to premaraviroc %CD38HLA-DR CD4 T-cells (Spearman = -0.52, P = 0.004), and lower premaraviroc HIV-1 DNA levels were associated with larger decreases in %CD38HLA-DR CD4 T-cells during maraviroc intensification (Spearman = 0.44, P = 0.018). Conclusion In individuals on suppressive ART with incomplete CD4 T-cell recovery, maraviroc intensification did not affect measures of HIV-1 persistence but did decrease persistent CD4 T-cell immune activation especially in individuals with low preintensification levels of HIV-1 DNA.

Vaccines hold promise both for the prevention of infections and as potential immunologic therapy for patients with autoimmune disease (AD). These patients are at high risk for both common and opportunistic infections, but this risk can be significantly reduced and even obviated with the use of recommended available vaccines. Unfortunately, patients with ADs are not routinely offered or provided indicated vaccinations and have higher rates of complications from vaccine-preventable illnesses than patients without ADs. In addition, vaccine therapy is currently under study for the treatment of autoimmune disorders, with early studies demonstrating immunomodulatory effects that may counter undesired immune activation and alleviate disease activity.

Study objectives There is a lack of epidemiologic information about duration of QRS complex in the general heart failure population. We sought to describe age, sex, and clinical subset specific prevalence of QRS prolongation in this population. Methods Data were abstracted from the Resource Utilization Among Congestive Heart Failure Study, which identified 29,686 patients with heart failure from a large, mixed-model managed-care organization during 1989 to 1999. A target population of 3,471 had echocardiographic data and ECG data obtained from automated sources during the first year of diagnosis. Systolic dysfunction was defined as heart failure plus a left ventricular ejection fraction Measurements and results Among the heart failure population, 20.8% of the subjects had a QRS duration ≥ 120 ms. A total of 425 men (24.7%) and 296 women (16.9%) had a prolonged QRS duration (p Conclusions Approximately 20% of a generalized heart failure population can be expected to have a prolonged QRS duration within the first year of diagnosis, suggesting that as many as 20% of patients with heart failure may be candidates for biventricular pacing.

Objectives Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/r) provides an alternative treatment option for HIV-1 infection that spares nucleoside analogs (NRTI) for future use and decreased toxicity. We hypothesized that the level of immune activation (IA) and recovery of lymphocyte populations could influence virologic outcomes after regimen simplification. Methods Thirty-four participants with virologic suppression ≥48 weeks on antiretroviral therapy (2 NRTI plus protease inhibitor) were switched to ATV/r alone in the context of the ACTG 5201 clinical trial. Flow cytometric analyses were performed on PBMC isolated from 25 patients with available samples, of which 24 had lymphocyte recovery sufficient for this study. Assessments included enumeration of T-cells (CD4/CD8), natural killer (NK) (CD3+CD56+CD16+) cells and cell-associated markers (HLA-DR, CD's 38/69/94/95/158/279). Results Eight of the 24 patients had at least one plasma HIV-1 RNA level (VL) >50 copies/mL during the study. NK cell levels below the group median of 7.1% at study entry were associated with development of VL >50 copies/mL following simplification by regression and survival analyses (p = 0.043 and 0.023), with an odds ratio of 10.3 (95% CI: 1.92–55.3). Simplification was associated with transient increases in naive and CD25+ CD4+ T-cells, and had no impact on IA levels. Conclusions Lower NK cell levels prior to regimen simplification were predictive of virologic rebound after discontinuation of nucleoside analogs. Regimen simplification did not have a sustained impact on markers of IA or T lymphocyte populations in 48 weeks of clinical monitoring. Trial Registration ClinicalTrials.gov NCT00084019

Background Routine HIV RNA clinical monitoring frequently reports virermia (VL) as detectable, quantifiable 50 c/mL. To assess whether the results represent true increases or just assay variability, we designed comparisons of the Roche COBAS AmpliPrep / COBAS TaqMan HIV-1 Test version 2.0 (TM) and the Abbott RealTime HIV-1 assay (RT) to a residual viremia (RV) assay with a limit of detection of 3 c/mL, the Modified Abbott Residual Viremia assay (MARV). Methods HIV suppressed patients on stable therapy presenting for routine visits at the HIV clinic in Henry Ford Hospital (HFH) were prospectively enrolled. Blood samples and questionnaires were obtained at each visit. Paired plasma samples were processed and analyzed per manufacturer instructions; HFH clinical laboratory processed the samples using the TM assay and the McKinnon Research Laboratory performed the FDA approved RT assay and RV testing using the MARV assay. Parametric and non-parametric analyses were conducted as indicated. Results 124 HIV patients are reported with a mean age of 51, mostly male (84%) and African American (64%). Mean CD4 cell counts were 661 cells/mm3. TM assay results for 196 plasma samples were not detectable (ND) 119 (61%), detectable (DT) 61 (31%) and quantifiable viremia (QV) >20 c/mL 16 (8%). 5 patients had QV over 50 c/mL. 60 tested patients (49.5%) had at least one sample either DT or QV. TM results were not correlated to CD4 cell counts, antiretrovirals, medical conditions or reported adherence (avg. 97%). 174 RT and 187 MARV paired tests were ND on 142 (81%) / 121 (65%), DT on 34 (17%) RT, and quantifiable in 0% / 34 (33%) of the samples respectively. Higher VL detection by the TM was shown compared with the RT (P = 0.005) and MARV (P < 0.001) assays. Mean QV by the MARV was 5.0 vs.. 55 c/mL on the TM assay (P < 0.001). VL for all assays trends correlated when compared for ND, DT and >20 copies/mL (P < 0.001). Bland-Altman plots show higher VL detected by TM as compared with MARV (P < 0.001) and good correlation between RT and MARV assays (P = 0.6). Conclusion HIV viremia is more frequently reported by TM assay as compared with the RT assay and was significantly higher than VL detected by the MARV assay. Over detection of VL by the TM assay may impact clinical decision making and increase cost of care. Disclosures J. Mckinnon, Abbott Molecular: Speaker’s Bureau, Grant recipient, Research grant and Speaker honorarium D. Lucic, Abbott Molecular: Employee, Salary

The majority of patients with suppression of human immunodeficiency virus type 1 (HIV-1) who are receiving antiretroviral therapy (ART) have substantial recovery of CD4+ T-cell counts, with a mean increase of 176 cells/µL (95% confidence interval [CI], 170–183) over the first year of treatment [1]. However, a French cohort study found that 17% of patients initiating a protease inhibitor–based regimen had an increase of 200 cells/µL, even after control for plasma HIV-1 RNA level [3]. Moreover, recent studies have established that CD4+ T-cell count is related to overall mortality and incidence of non–AIDS-defining cancer, even among subjects with a CD4+ T-cell count of >350 cells/µL [4, 5]. A meta-regression of phase 2 and 3 clinical trials of investigational ART agents found that the increase in CD4+ T-cell count in groups using a CCR5 antagonist was 30 cells/µL higher than that in groups not using a CCR5 antagonist, after control for differing rates of virologic suppression [6]. Similarly, greater recovery in CD4+ T-cell count was observed in a phase 3 trial comparing combination regimens with maraviroc, a CCR5 antagonist, or with efavirenz, a nonnucleoside reverse-transcriptase inhibitor (NNRTI), for initial ART of HIV-1–infected patients [7]. While maraviroc did not meet prespecified criteria in that study for a noninferiority comparison with efavirenz for virologic suppression, subjects receiving maraviroc had a significantly greater increase in CD4+ T-cell count 48 weeks after randomization as compared to those receiving efavirenz (change from baseline, +170 vs +144 cells/µL; difference, 26 cells/µL [95% CI, 7–46]) [7]. Given the potential benefit of maraviroc on CD4+ T-cell recovery, we designed and conducted AIDS Clinical Trials Group (ACTG) protocol A5256, a single-arm, multicenter, open-label clinical trial designed to test the hypothesis that adding the CCR5 inhibitor maraviroc will result in a CD4+ T-cell count increase of at least 20 cells/µL over 24 weeks in ART recipients with a rigorously defined suboptimal CD4+ T-cell recovery despite sustained virologic suppression.

Current U.S. guidelines for initial therapy of HIV type-1 (HIV-1) infection recommend daily, lifelong treatment with a combination of three antiretroviral drugs consisting of two nucleoside analogue reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor. Although this approach has been successful in reducing morbidity and mortality from HIV-1 infection, concerns remain about adverse events from chronic drug exposure, the requirement for daily medication adherence, the risk of HIV-1 drug resistance and high treatment costs. The availability of antiretrovirals that are coformulated and dosed once daily have reduced pill burden and have simplified dosing schedules, but have not lowered drug exposure or cost. These limitations have stimulated research into drug-sparing strategies including intermittent therapy and simplified maintenance regimens. Randomized clinical trials have shown greater mortality with intermittent therapy compared with continuous therapy leading to rejection of this strategy. Pilot studies of simplified maintenance therapy with a ritonavir-boosted protease inhibitor alone have shown more promise, although concerns remain. This article reviews progress in the simplification of antiretroviral therapy, recent clinical trial results and prospects for the future.

Simplified maintenance therapy with ritonavir-boosted atazanavir (ATV/RTV) alone is attractive because of nucleoside reverse-transcriptase inhibitor (NRTI)-sparing benefits, low pill burden, once-daily dosage, and safety.Subjects with virologic suppression afteror = 48 weeks of initial antiretroviral therapy with 2 NRTIs and a protease inhibitor (PI) were enrolled. Subjects switched to ATV/RTV at entry and discontinued NRTIs after 6 weeks. The primary end point was time to virologic failure (confirmed HIV-1 RNA levelor = 200 copies/mL). Drug resistance at virologic failure was evaluated by standard genotyping and single-genome sequencing (SGS). Residual viremia (1.1-49 copies/mL) was measured by single-copy assay.Thirty-four subjects simplified to ATV/RTV alone, of whom 30 (88%) did not experience virologic failure by 48 weeks after simplification. Residual viremia did not change significantly after NRTI discontinuation among those without virologic failure but did increase 4-12 weeks before confirmed virologic failure. No major PI-resistance mutations were identified at virologic failure by standard genotyping or SGS.In this pilot study, simplified maintenance therapy with ATV/RTV alone maintained viral suppression in most subjects through 48 weeks. PI resistance was not detected among subjects experiencing virologic failure. Larger, randomized trials are warranted to further define the efficacy and safety of this strategy.

Background In recent studies, subjects who had achieved suppression of the human immunodeficiency virus (HIV) RNA level while receiving an initial 3-drug antiretroviral regimen successfully maintained suppression while receiving treatment with a "boosted" protease inhibitor (PI) alone. We projected the long-term outcomes of this treatment simplification strategy to inform the design of a proposed multicenter, randomized clinical trial. Methods We used published studies to estimate the efficacy, adverse effects, and cost of a sequence of HIV drug regimens for the simplification strategy, compared with those outcomes for the current standard-of-care (SOC) strategy. Using a published simulation model of HIV disease, we projected life expectancy, discounted quality-adjusted life expectancy (QALE), and discounted lifetime medical costs for each strategy. Results Subjects who have not developed PI-resistant HIV infection at the time of failure of the simplification regimen have a greater life expectancy (27.9 vs. 27.1 years) and QALE (14.9 vs. 14.7 years), compared with SOC subjects, because they receive an additional line of therapy without negative consequences for future treatment options. The QALE for the simplification strategy remains higher than that for the SOC, unless a large proportion of patients experiencing virologic failure while receiving the simplification regimen develop PI resistance. Depending on the probability of simplification regimen failure, the advantage is maintained even if HIV develops PI resistance in 42%-70% of subjects. Projected lifetime costs are $26,500-$72,400 per person lower for the simplification strategy than for the SOC strategy. Conclusions An HIV treatment simplification strategy involving use of a boosted PI alone may lead to longer survival overall at lower cost, compared with the SOC combination therapy, because the simplification strategy potentially adds an additional line of therapy. The risk of emergence of PI resistance during treatment with a simplified regimen is a critical determinant of the viability of this strategy.

OBJECTIVE To determine whether the level of persistent HIV-1 viremia is affected by simplifying standard antiretroviral therapy to lopinavir/ritonavir (LPV/r) alone. DESIGN Measurement of HIV-1 RNA levels < 50 copies/ml in longitudinal plasma samples from 41 of 42 subjects enrolled in the 'Only Kaletra' study that compared maintenance therapy with LPV/r alone to standard of care (SOC) with two nucleoside reverse transcriptase inhibitors (NRTI) and LPV/r. METHODS Plasma samples for each subject from study screening to week 48 were tested using a modified Roche Amplicor HIV-1 RNA assay with a quantification limit of 3 copies/ml. RESULTS Median plasma HIV-1 RNA values at baseline and weeks 4, 8, 12, 24 and 48 were not significantly different between the LPV/r alone and the SOC arms, being 5.1 versus 3.0 (P = 0.29), 4.5 versus 2.9 (P = 0.44), 3.3 versus 2.9 (P = 0.99), 1.9 versus 1.0 (P = 0.68), 3.7 versus 3.6 (P = 0.49), and 2.8 versus 1.6 copies/ml (P = 0.78), respectively. In the 17 of 21 subjects who maintained virus suppression < 50 copies/ml on LPV/r alone, median HIV-1 RNA values did not increase significantly from baseline at any time point after discontinuing NRTI, in comparison to the three subjects with virologic failure whose median HIV-1 RNA levels began to rise at week 8. CONCLUSIONS The level of persistent viremia did not increase after stopping NRTI therapy among subjects who maintained virus suppression < 50 copies/ml on LPV/r alone through 48 weeks. This supports further studies of induction-simplification therapy for treatment of HIV-1 infection including the identification of factors predicting success or failure of simplified therapy.

ContextThe long-term adverse effects, expense, and difficulty of adherence to antiretroviral regimens have led to studies of simpler maintenance therapies. Maintenance therapy with ritonavir-boosted atazanavir alone is a possible option because of low pill burden, once-daily dosing, safety, and unique resistance profile.ObjectiveTo assess whether simplified maintenance therapy with atazanavir-ritonavir alone after virologic suppression increases the risk of virologic failure (2 consecutive human immunodeficiency virus type 1 [HIV-1] RNA measurements of ≥200 copies/mL).Design, Setting, and ParticipantsSingle-group, open-label, multicenter, 24-week pilot study of 36 HIV-infected adults with virologic suppression for 48 weeks or longer receiving their first protease inhibitor (PI)–based regimen. The study was conducted between September 1, 2004, and April 18, 2006, at 12 participating AIDS clinical trial units in the United States.InterventionParticipants switched PIs to atazanavir-ritonavir at entry and discontinued nucleoside analog reverse transcriptase inhibitors (NRTIs) after 6 weeks.Main Outcome MeasuresVirologic failure within 24 weeks of discontinuing NRTIs. Other measures included HIV-1 drug resistance, plasma atazanavir concentrations, adverse events, CD4 cell counts, plasma lipid levels, and HIV-1 RNA levels in seminal plasma.ResultsThirty-six participants enrolled and 2 discontinued before simplification to atazanavir-ritonavir alone. Thirty-four patients were included in the analysis of the primary end point after 24 weeks: 1 withdrew voluntarily, and 33 continued the regimen. Virologic success (absence of failure) through 24 weeks of simplified therapy occurred in 91% (31 of 34 patients; lower 90% confidence interval limit = 85%). Three participants experienced virologic failure 12, 14, and 20 weeks after simplification, with plasma HIV-1 RNA levels of 4730, 1285, and 28 397 copies/mL, respectively. Resistance testing at failure did not identify PI resistance mutations. Plasma atazanavir concentrations at failure were low or below detection in 2 of 3 participants experiencing failure. There were no treatment discontinuations for adverse events after simplification; no significant changes in CD4 cell counts or plasma lipid levels; and no detectable HIV-1 RNA in seminal plasma from all 8 participants tested.ConclusionsThese preliminary data suggest that simplified maintenance therapy with atazanavir-ritonavir alone may be efficacious for maintaining virologic suppression in carefully selected patients with HIV infection. These findings require confirmation in larger, randomized trials of this strategy.Trial Registrationclinicaltrials.gov Identifier: NCT00084019

We sought to describe a large heart failure (HF) population with respect to systolic and diastolic abnormalities in terms of demographics, echocardiographic parameters, and survival. Using data abstracted from the Resource Utilization Among Congestive Heart Failure (REACH) study, a targeted subpopulation of 3471 patients had electrocardiographic, echocardiographic, and clinical data taken from automated sources during the first year of diagnosis. Among the HF population, 1811 (52.2%) had diastolic HF. Prevalence of diastolic HF trended with age, from 46.4% in those less than 45 years to 58.7% in those 85 years or older (p=0.001 for trend). Patients with diastolic HF had a higher mean ejection fraction (55.7% vs. 28.0%), lower left ventricular end-systolic diameter (3.11 vs. 4.74 cm), and lower left atrium:aortic outlet ratio (1.28 vs. 1.38) (p=0.001 for each comparison). Annualized age, sex, and race-adjusted mortality were 11.2% and 13.0% for those with diastolic and systolic HF, respectively (p=0.001). In a large, racially mixed, urban HF population, those with diastolic HF predominate and enjoy better-adjusted survival than counterparts with systolic HF.