Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide discontinuation and return to normal weight.

HIV integrase strand transfer inhibitors (INSTI) are considered well tolerated with few treatment-limiting adverse effects. However, emerging data from clinical trials has identified excessive weight gain possibly due to INSTI alone or with tenofovir alafenamide as a new and possible long-term complication of combination antiretroviral therapy (cART). Identifying who is at greatest risk and whether the unintended weight gain is reversible remain unanswered questions. We report a return to baseline weight after switching back to tenofovir disoproxil/emtricitabine/efavirenz (Atripla®) in a woman who had profound weight gain due to tenofovir alafenamide/emtricitabine/cobicistat/elvitegravir (Genvoya®).

HIV-1 Virologic Rebound Due to Coadministration of Divalent Cations and Bictegravir.

A potential drug-drug interaction exists between divalent and trivalent cations (Ca2+, Fe3+, Mg2+, Al3+, Zn2+) and HIV-1 integrase strand transfer inhibitors (INSTIs). There are limited case reports describing the clinical significance of this potential interaction and none to our knowledge identifying zinc co-administration with INSTIs. In this report we present a patient taking bictegravir/emtricitabine/tenofovir alafenamide who became viremic after ingesting zinc and calcium supplements and later was able to obtain virologic re-suppression after discontinuing supplements. This case represents a potential significant drug interaction between a commonly prescribed antiretroviral drug class and readily available over-the-counter divalent cation products.

The importance of skin exam in chronic pulmonary blastomycosis.

Cutaneous blastomycosis is the most common extrapulmonary manifestation of disseminated blastomycosis, a disease caused by Blastomyces dermatitidis, a dimorphic fungus endemic of North America. Initially, the organism enters the respiratory system by inhalation of the infectious conidia and produces an acute pulmonary infection that may eventually disseminate if it is left untreated. Blastomycosis may represent a diagnostic challenge and its definitive diagnosis requires direct visualization of the distinctive yeast or a positive fungal culture. The objective of this case report is to highlight the importance of the skin exam and tissue biopsy in the diagnosis of blastomycosis. We present a previously healthy patient with chronic pneumonia, evaluated at Pulmonary clinic with non-diagnostic thoracentesis and bronchoscopy, found to have disseminated blastomycosis after biopsy of a scalp lesion in Dermatology clinic.

Disseminated Cryptococcal Disease in a Patient with Chronic Lymphocytic Leukemia on Ibrutinib.

Cryptococcus is a unique environmental fungus that can cause disease most often in immunocompromised individuals with defective cell-mediated immunity. Chronic lymphocytic leukemia (CLL) is not known to be a risk factor for cryptococcal disease although cases have been described mainly in patients treated with agents that suppress cell-mediated immunity. Ibrutinib is a new biologic agent used for treatment of CLL, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. It acts by inhibiting Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor critical for B-cell survival and proliferation. Ibrutinib use has not been associated previously with cryptococcal disease. However, recent evidence suggested that treatments aimed at blocking the function of Bruton's tyrosine kinase could pose a higher risk for cryptococcal infection in a mice model. Here, we report the first case of disseminated cryptococcal disease in a patient with CLL treated with ibrutinib. When evaluating possible infection in CLL patients receiving ibrutinib, cryptococcal disease, which could be life threatening if overlooked, could be considered.

Role of the Infectious Disease Consultant in Management of Patients With Tuberculosis-Associated Ocular Inflammation.

Background. Tuberculosis is a disease with continued worldwide prevalence, morbidity, and mortality. Tuberculosis-associated ocular inflammation (TB-AOI) is a manifestation that can occur with pulmonary or extrapulmonary TB. Evaluation of these ocular presentations and treatment in the United States are limited. Our objective was to describe cases in an urban area and assess the role of the infectious diseases specialist in managing these complex patients. Methods. We performed a retrospective case series of all patients referred to our infectious disease clinic for presumed TB-AOI from 2005 through 2013. Patients with ocular inflammation were determined to have presumed TB-AOI based on clinical presentation with correlative positive tuberculin skin test and/or QuantiFERON-TB Gold. Attempts were made to exclude other diagnoses. Data were collected and analyzed with respect to demographics, ocular manifestations, and treatment. Results. Sixty eyes of 42 patients were included in the study; anterior uveitis was the most common site of involvement. The median age was 46 years, and 33 patients (79%) were foreign born. Forty patients (95%) received a course of antituberculous therapy with 38% experiencing treatment-related side effects. A 6-month duration was recommended in 78% cases. There was improvement or stability of the vision in 42 eyes (74%) of those treated. Conclusions. Ocular involvement is an uncommon but important manifestation of TB. Our data further characterize TB-AOI cases in the United States. Treatment provides significant benefit to properly selected patients. A multidisciplinary approach, with care provided by ophthalmology and infectious disease providers, should be used to allow for the most efficacious treatment.

HIV-associated mucosal gene expression: region-specific alterations.

OBJECTIVE: Despite the use of HAART to control HIV, systemic immune activation and inflammation persists with the consequence of developing serious non-AIDS events. The mechanisms that contribute to persistent systemic immune activation have not been well defined. The intestine is the major source of "sterile" inflammation and plays a critical role in immune function; thus, we sought to determine whether intestinal gene expression was altered in virally controlled HIV-infected individuals. DESIGN AND METHODS: Gene expression was compared in biopsy samples collected from HIV-uninfected and HIV-infected individuals from the ileum, right colon (ascending colon), and left colon (sigmoid). Affymetrix gene arrays were performed on tissues and pathway analyses were conducted. Gene expression was correlated with systemic markers of intestinal barrier dysfunction and inflammation and intestinal microbiota composition. RESULTS: Genes involved in cellular immune response, cytokine signaling, pathogen-influenced signaling, humoral immune response, apoptosis, intracellular and second messenger signaling, cancer, organismal growth and development, and proliferation and development were upregulated in the intestine of HIV-infected individuals with differences observed in the ileum, right, and left colon. Gene expression in the ileum primarily correlated with systemic markers of inflammation (e.g., IL7R, IL2, and TLR2 with serum TNF) whereas expression in the colon correlated with the microbiota community (e.g., IFNG, IL1B, and CD3G with Bacteroides). CONCLUSION: These data demonstrate persistent, proinflammatory changes in the intestinal mucosa of virally suppressed HIV-infected individuals. These changes in intestinal gene expression may be the consequence of or contribute to barrier dysfunction and intestinal dysbiosis observed in HIV.

A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects.

HIV progression is characterized by immune activation and microbial translocation. One factor that may be contributing to HIV progression could be a dysbiotic microbiome. We therefore hypothesized that the GI mucosal microbiome is altered in HIV patients and this alteration correlates with immune activation in HIV. 121 specimens were collected from 21 HIV positive and 22 control human subjects during colonoscopy. The composition of the lower gastrointestinal tract mucosal and luminal bacterial microbiome was characterized using 16S rDNA pyrosequencing and was correlated to clinical parameters as well as immune activation and circulating bacterial products in HIV patients on ART. The composition of the HIV microbiome was significantly different than that of controls; it was less diverse in the right colon and terminal ileum, and was characterized by loss of bacterial taxa that are typically considered commensals. In HIV samples, there was a gain of some pathogenic bacterial taxa. This is the first report characterizing the terminal ileal and colonic mucosal microbiome in HIV patients with next generation sequencing. Limitations include use of HIV-infected subjects on HAART therapy.

A role for TLR signaling during B cell activation in antiretroviral-treated HIV individuals.

The mechanisms underlying B cell activation that persists during antiretroviral therapy (ART) are unknown. Toll-like receptor (TLR) signaling is a critical mediator of innate cell activation and though B cells express TLRs, few studies have investigated a role for TLR signaling in B cell activation during HIV infection. We addressed this question by assessing the activated phenotype and TLR expression/responsiveness of B cells from ART-treated HIV-infected subjects (HIVART(+)). We evaluated activation markers implicated in B cell-mediated T cell trans infection during HIV pathogenesis. We found no significant difference in TLR expression between B cells of HIVART(+) and HIV(-) subjects. However, B cells of HIVART(+) subjects exhibited heightened endogenous expression levels of IL-6 (p=0.0051), T cell cognate ligands CD40 (p=0.0475), CD54 (p=0.0229), and phosphorylated p38 (p<0.0001), a marker of TLR signaling. In vitro, B cells of HIVART(+) individuals were less responsive to TLR stimulation compared to B cells of HIV(-) subjects. The activated phenotype of in vitro TLR-stimulated B cells of HIV(-) subjects was similar to ex vivo B cells from HIVART(+) individuals. TLR2 stimulation was a potent mediator of B cell activation, whereas B cells were least responsive to TLR4 stimulation. Compared to HIV(-) subjects, the serum level of lipoteichoic acid (TLR2 ligand) in HIVART(+) subjects was significantly higher (p=0.0207), correlating positively with viral load (p=0.0127, r=0.6453). Our data suggest that during HIV infection TLR-activated B cells may exert a pathogenic role and B cells from HIVART(+) subjects respond to in vitro TLR stimulation, yet exhibit a TLR tolerant phenotype suggesting prior in vivo TLR stimulation.

Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8⁺ T cell function in vitro.

HIV infection is associated with elevated expression of IL-10 and PD-L1, contributing to impairment of T cell effector functions. In autoimmunity, tumor immunology, and some viral infections, Bregs modulate T cell function via IL-10 production. In this study, we tested the hypothesis that during HIV infection, Bregs attenuate CD8(+) T cell effector function, contributing to immune dysfunction. We determined that in vitro, TLR2-, TLR9-, and CD40L-costimulated Bregs from HIV(-) individuals exhibited a high frequency of cells expressing IL-10 and PD-L1. Compared with Bregs from HIV(-) individuals, a significantly higher percentage of Bregs from HIV(+) individuals spontaneously expressed IL-10 (P=0.0218). After in vitro stimulation with HIV peptides, Breg-depleted PBMCs from HIV(+) individuals exhibited a heightened frequency of cytotoxic (CD107a(+); P=0.0171) and HIV-specific CD8(+) T cells compared with total PBMCs. Furthermore, Breg depletion led to enhanced proliferation of total CD8(+) and CD107a(+)CD8(+) T cells (P=0.0280, and P=0.0102, respectively). In addition, augmented CD8(+) T cell effector function in vitro was reflected in a 67% increased clearance of infected CD4(+) T cells. The observed Breg suppression of CD8(+) T cell proliferation was IL-10-dependent. In HIV(+) individuals, Breg frequency correlated positively with viral load (r=0.4324; P=0.0095), immune activation (r=0.5978; P=0.0005), and CD8(+) T cell exhaustion (CD8(+)PD-1(+); r=0.5893; P=0.0101). Finally, the frequency of PD-L1-expressing Bregs correlated positively with CD8(+)PD-1(+) T cells (r=0.4791; P=0.0443). Our data indicate that Bregs contribute to HIV-infection associated immune dysfunction by T cell impairment, via IL-10 and possibly PD-L1 expression.

An educational intervention to improve antimicrobial use in a hospital-based long-term care facility.

OBJECTIVES: To improve antimicrobial use in patients receiving long-term care (LTC). DESIGN: Prospective, quasi-experimental before-after assessment of the effects of physician education and guideline implementation. SETTING: Public LTC and acute care hospital. PARTICIPANTS: Twenty salaried internists who provided most of the medical care to LTC patients. INTERVENTION: National guidelines, hospital resistance data, and physician feedback were incorporated into a series of four teaching sessions presented over 18 months and into booklets detailing institutional guidelines on the optimal management of common LTC infection syndromes. MEASUREMENTS: One hundred randomly selected LTC patients treated with antimicrobials were reviewed before these interventions were implemented and 100 after, and measures of the quality of care were compared. The effect of the interventions on antimicrobial days and starts were also assessed using interrupted time series analysis. RESULTS: Charted clinical abnormalities met guideline diagnostic criteria (62% vs 38%, P=.006), and initial therapy agreed with guideline recommendations (39% vs 11%, P<.001), more often in the post- than in the preintervention cohort. Mean census-adjusted monthly LTC antimicrobial days fell 29.7%, and antimicrobial starts fell 25.9% during the intervention period; both decreases were sustained during the 2-year postintervention period. CONCLUSION: The teaching and guideline intervention improved the quality and reduced the quantity of antimicrobial use in LTC patients.

Multicenter intervention program to increase adherence to hand hygiene recommendations and glove use and to reduce the incidence of antimicrobial resistance.

OBJECTIVE: To determine whether a multimodal intervention could improve adherence to hand hygiene and glove use recommendations and decrease the incidence of antimicrobial resistance in different types of healthcare facilities. DESIGN: Prospective, observational study performed from October 1, 1999, through December 31, 2002. We monitored adherence to hand hygiene and glove use recommendations and the incidence of antimicrobial-resistant bacteria among isolates from clinical cultures. We evaluated trends in and predictors for adherence and preferential use of alcohol-based hand rubs, using multivariable analyses. SETTING: Three intervention hospitals (a 660-bed acute and long-term care hospital, a 120-bed community hospital, and a 600-bed public teaching hospital) and a control hospital (a 700-bed university teaching hospital).Intervention. At the intervention hospitals, we introduced or increased the availability of alcohol-based hand rub, initiated an interactive education program, and developed a poster campaign; at the control hospital, we only increased the availability of alcohol-based hand rub. RESULTS: We observed 6,948 hand hygiene opportunities. The frequency of hand hygiene performance or glove use significantly increased during the study period at the intervention hospitals but not at the control hospital; the maximum quarterly frequency of hand hygiene performance or glove use at intervention hospitals (74%, 80%, and 77%) was higher than that at the control hospital (59%). By multivariable analysis, preferential use of alcohol-based hand rubs rather than soap and water for hand hygiene was more likely among workers at intervention hospitals compared with nonintervention hospitals (adjusted odds ratio, 4.6 [95% confidence interval, 3.3-6.4]) and more likely among physicians (adjusted odds ratio, 1.4 [95% confidence interval, 1.2-1.8]) than among nurses at intervention hospitals. A significantly reduced incidence of antimicrobial-resistant bacteria among isolates from clinical culture was found at a single intervention hospital, which had the greatest increase in the frequency of hand hygiene performance. CONCLUSIONS: During a 3-year period, a multimodal intervention program increased adherence to hand hygiene recommendations, especially to the use of alcohol-based hand rubs. In one hospital, a concomitant reduction was found in the incidence of antimicrobial-resistant bacteria among isolates from clinical cultures.

Comparison of routine glove use and contact-isolation precautions to prevent transmission of multidrug-resistant bacteria in a long-term care facility.

OBJECTIVES: To compare routine glove use by healthcare workers for all residents, without use of contact-isolation precautions, with contact-isolation precautions for the care of residents who had vancomycin-resistant enterococci or methicillin-resistant Staphylococcus aureus isolated from a clinical culture. DESIGN: Random allocation of two similar sections of the skilled-care unit to one of the infection-control strategies during an 18-month study period. SETTING: Skilled-care unit of a 667-bed acute- and long-term care facility. PARTICIPANTS: All residents present or admitted to the skilled-care unit from June 1, 1998, through December 7, 1999. MEASUREMENTS: Resident acquisition of four antimicrobial-resistant organisms (methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, or extended-spectrum beta-lactamase-producing Klebsiella pneumoniae or Escherichia coli). All isolates were strain typed. The facility level costs associated with each strategy were estimated. RESULTS: Resident acquisition of antimicrobial-resistant organisms was no different in the glove-use and isolation-precautions sections (31 episodes (1.5 per 1,000 resident-days) vs 38 episodes (1.6 per 1,000 resident-days)). Acquisition of either of two prevalent K. pneumoniae strains was more likely (P=.06) in residents in the isolation-precautions section. The estimated costs of contact-isolation precautions were 40% greater than those of routine glove use. CONCLUSION: There was a similar frequency of transmission of antimicrobial-resistant bacteria in the two study sections; there was evidence for resident-to-resident K. pneumoniae transmission in the isolation-precautions section. Routine glove use for healthcare workers, which decreases resident social isolation and healthcare facility costs, may be preferable in many long-term care facilities.

Epidemiology and outcome of Clostridium difficile infection and diarrhea in HIV infected inpatients.

Clostridium difficile causes diarrhea in HIV infected patients but reports of prevalence, risk factors, and outcome vary. We studied the impact of C. difficile in 161 HIV infected inpatients admitted to Cook County Hospital. Patients with C. difficile had more hospital admissions in the previous 6 months (p =.04), spent more days in the hospital in the previous 3 months (p =.02), more often had previously received H2 blockers or treatment for Pneumocystis carinii (p <.05), and had a more frequent history of herpesvirus (p =.03) or opportunistic infections (p =.04). C. difficile associated diarrhea (CDAD) was the etiology in 32% of all study patients with diarrhea. Patients with CDAD were hospitalized for longer periods (p =.02) and received more antibiotics (p =.002). C. difficile was frequently present in our HIV infected patients, especially those with advanced HIV disease, but appeared to have little impact on morbidity or mortality.