Search

Objectives: This study's primary objective was to characterize attitudes to long-acting antiretrovirals (LAARV), among youth aged 13-24 years living with perinatally acquired HIV and nonperinatally acquired HIV. Secondary objectives included: assessing whether those with detectable HIV RNA PCR viral load had higher enthusiasm for LAARV compared to those with suppressed viral load, and examining characteristics associated with LAARV enthusiasm., Methods: A cross-sectional survey of 303 youth living with HIV (YHIV) followed at 4 pediatric/adolescent HIV clinics in the United States was performed to determine interest in LAARV, using a modified survey instrument previously used in adults. Interest in LAARV across groups was compared. Poisson regression with robust variance was used to determine the impact of various characteristics on interest in LAARV., Findings: Overall, 88% of YHIV reported probable or definite willingness to use LAARV. The enthusiasm level was similar between youth with perinatally acquired HIV and nonperinatally acquired HIV (P = 0.93). Youth with HIV viral load >1000 copies per milliliter had significantly higher interest than youth with suppressed viral load [prevalence ratio 1.12 (95% confidence interval: 1.03 to 1.20); P = 0.005]. Female youth participants who had had past experience with implantable contraceptive methods had a significantly higher interest in LAARV (100% vs. 85.5%; P = 0.002). Proportion of respondents endorsing definite willingness to use was significantly higher with decreased injection frequency compared with increased injection frequency., Interpretation: YHIV at 4 urban US pediatric/adolescent HIV clinics had high levels of enthusiasm for LAARV. LAARV should be given high priority as a potentially viable treatment option to improve clinical outcomes in YHIV.

Purpose of Review: Long-acting parenteral drug delivery is an established and widely accepted solution to the problem of poor adherence when daily oral medications are used to treat or prevent chronic medical conditions. Poor adherence to oral formulations remains a major barrier to successfully treating or preventing HIV, tuberculosis (TB), and viral hepatitis. The uptake of long-acting formulations developed for these infections is uncertain, despite their promise. This review addresses the current state of development of long-acting and extended-release approaches to HIV, TB, and viral hepatitis in the context of creating market demand for such products., Recent Findings: Two nanoformulated long-acting injectable antiretroviral compounds, cabotegravir and rilpivirine, recently completed Phase 2 clinical trials demonstrating safety, tolerability, and antiretroviral activity, and should be available in high income countries following completion of ongoing Phase 3 trials. Long-acting polymer implants of the antiretroviral nucleosides tenofovir alafenamide and 4'-ethynyl-2-fluoro-2'-deoxyadenosine are being tested in animals and should soon enter human studies; tenofovir alafenamide also has activity against hepatitis B virus. Long-acting versions of several broadly neutralizing monoclonal antibodies are in advanced clinical trials for HIV prevention and treatment. Long-acting formulations for TB are in preclinical development. There is no evidence that comparable formulations for viral hepatitis are being developed at present., Summary: Long-acting and extended release formulations are promising approaches to the treatment and prevention of common infectious diseases, but their availability is limited at this time. These products hold great promise for the global control of important human infections. Based on experience with other diseases, it is likely that their use will become more widespread if they are cost competitive with generic oral formulations.

Setting: The household contacts (HHCs) of multidrug-resistant tuberculosis (MDR-TB) index cases are at high risk of tuberculous infection and disease progression, particularly if infected with the human immunodeficiency virus (HIV). HIV testing is important for risk assessment and clinical management., Methods: This was a cross-sectional, multi-country study of adult MDR-TB index cases and HHCs. All adult and child HHCs were offered HIV testing if never tested or if HIV-negative >1 year previously when last tested. We measured HIV testing uptake and used logistic regression to evaluate predictors., Results: A total of 1007 HHCs of 284 index cases were enrolled in eight countries. HIV status was known at enrolment for 226 (22%) HHCs; 39 (4%) were HIV-positive. HIV testing was offered to 769 (98%) of the 781 remaining HHCs; 544 (71%) agreed to testing. Of 535 who were actually tested, 26 (5%) were HIV-infected. HIV testing uptake varied by site (median 86%, range 0-100%; P < 0.0001), and was lower in children aged <18 years than in adults (59% vs. 78%; adjusted for site P < 0.0001)., Conclusions: HIV testing of HHCs of MDR-TB index cases is feasible and high-yield, with 5% testing positive. Reasons for low test uptake among children and at specific sites-including sites with high HIV prevalence-require further study to ensure all persons at risk for HIV are aware of their status.

Introduction: Pharmacist provision of pre-exposure prophylaxis (PrEP) through collaborative practice agreements with physicians could expand access to people at risk for HIV. We characterized pharmacists' familiarity with and willingness to provide PrEP services in Nebraska and Iowa., Methods: An invitation to complete an 18-question survey was emailed to 1,140 pharmacists in Nebraska and Iowa in June and July of 2016. Descriptive analyses and Pearson chi-square tests were used to determine to what extent demographics, familiarity and experience were associated with respondent willingness to provide PrEP. Wilcoxon rank-sum tests compared ages and years of experience between groups of respondents., Results: One hundred forty pharmacists (12.3%) responded. Less than half were familiar with the use of PrEP (42%) or the CDC guidelines for its use (25%). Respondents who were older (p = .015) and in practice longer (p = .005) were less likely to be familiar with PrEP. Overall, 54% indicated they were fairly or very likely to provide PrEP services as part of a collaborative practice agreement and after additional training. While familiarity with PrEP use or guidelines did not affect respondents' willingness to provide PrEP, respondents were more likely to provide PrEP with prior experience counseling HIV-infected patients on antiretroviral therapy (OR 2.43; p = 0.023) or PrEP (OR 4.67; p = 0.013), and with prior HIV-related continuing education (OR 2.77; p = 0.032)., Conclusions: Pharmacist respondents in Nebraska and Iowa had limited familiarity and experience with PrEP, but most indicated willingness to provide PrEP through collaborative practice agreements after additional training. Provision of PrEP-focused continuing education may lead to increased willingness to participate in PrEP programs., Competing Interests: SHB reports research grants to her institution from Gilead Sciences. SS reports research grants to her institution from ViiV and Merck. All other authors report no potential conflicts. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To identify the neural markers of attention dysfunction in patients with HIV-associated neurocognitive disorder (HAND)., Methods: Sixty participants, including 40 HIV-infected adults (half with HAND) and 20 demographically matched controls performed a visual selective attention task while undergoing high-density magnetoencephalography. Neuronal activity related to selective attention processing was quantified and compared across the 3 groups, and correlated with neuropsychological measures of attention and executive function. Spontaneous neural activity was also extracted from these attention-related cortical areas and examined with respect to HAND status., Results: HIV-infected participants with and without HAND exhibited behavioral selective attention deficits on the magnetoencephalography task, as indicated by an increased flanker effect. Neuronal measures of flanker interference activity in the alpha and theta range revealed differential dynamics in attention-related brain areas across the 3 groups, especially in those with HAND. In addition, theta range flanker interference activity in the left inferior frontal and dorsolateral prefrontal cortex was associated with executive function and attention composite scores, respectively. Progressively stronger spontaneous alpha and theta activity was also found in unimpaired HIV-infected and HAND participants relative to controls across brain regions implicated in different components of attention processing., Conclusions: Behavioral and neuronal metrics of selective attention performance distinguish participants with HAND from controls and unimpaired HIV-infected participants. These metrics, along with measures of local spontaneous neural activity, may hold promise as early markers of cognitive decline in participants with HIV infection and be useful prognostic indicators for HAND., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Current guidelines recommend evaluation of the household contacts (HHCs) of individuals with multidrug-resistant tuberculosis (MDR-TB); however, implementation of this policy is challenging., Objective: To describe the resource utilization and operational challenges encountered when identifying and characterizing adult MDR-TB index cases and their HHCs., Design: Cross-sectional study of adult MDR-TB index cases and HHCs at 16 clinical research sites in eight countries. Site-level resource utilization was assessed with surveys., Results: Between October 2015 and April 2016, 308 index cases and 1018 HHCs were enrolled. Of 280 index cases with sputum collected, 94 were smear-positive (34%, 95%CI 28-39), and of 201 with chest X-rays, 87 had cavitary disease (43%, 95%CI 37-50) after a mean duration of treatment of 8 weeks. Staff required 512 attempts to evaluate the 308 households, with a median time per attempt of 4 h; 77% (95%CI 73-80) of HHCs were at increased risk for TB: 13% were aged <5 years, 8% were infected with the human immunodeficiency virus, and 79% were positive on the tuberculin skin test/interferon-gamma release assay. One hundred and twenty-one previously undiagnosed TB cases were identified. Issues identified by site staff included the complexity of personnel and participant transportation, infection control, personnel safety and management of stigma., Conclusion: HHC investigations can be high yield, but are labor-intensive.

While the arrival of combination antiretroviral therapy significantly decreased the prevalence of HIV-associated dementia, between 35 and 70% of all infected adults continue to develop some form of cognitive impairment. These deficits appears to affect multiple neural subsystems, but the mechanisms and extent of damage are not fully understood. In the current study, we utilized magnetoencephalography (MEG), advanced oscillatory analysis methods, and a paired-pulse somatosensory stimulation paradigm to interrogate pre-attentive inhibitory processing in 43 HIV-infected adults and 28 demographically-matched uninfected controls. MEG responses were imaged using a beamformer, and time series data were extracted from the peak voxel in grand-averaged functional brain images to quantify the dynamics of sensory gating, oscillatory power, spontaneous power, and other neural indices. We found a significantly weakened response to the second stimulation compared to the first across groups, indicating significant sensory gating irrespective of HIV-infection. Interestingly, HIV-infected participants exhibited reduced neural responses in the 20-75 Hz gamma range to each somatosensory stimulation compared to uninfected controls, and exhibited significant alterations in peak gamma frequency in response to the second stimulation. Finally, HIV-infected participants also had significantly stronger spontaneous activity in the gamma range (i.e., 20-75 Hz) during the baseline period before stimulation onset. In conclusion, while HIV-infected participants had the capacity to efficiently gate somatosensory input, their overall oscillatory responses were weaker, spontaneous baseline activity was stronger, and their response to the second stimulation had an altered peak gamma frequency. We propose that this pattern of deficits suggests dysfunction in the somatosensory cortices, which is potentially secondary to accelerated aging.

Background: Tenofovir alafenamide (TAF) is associated with less renal and bone toxicity compared with tenofovir disoproxil (TDF). TAF's recent FDA approval has spurred HIV providers to consider switching antiretroviral therapy (ART) regimens containing TDF to TAF to minimize long term risks. Patient views on the process of such medication switches have not been explored., Methods: Patients taking elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) following the Food and Drug Administration's (FDA) approval of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) received medication education from an HIV pharmacist prior to switching to the tenofovir alafenamide (TAF) formulation. Patients were asked to complete a cross-sectional survey assessing satisfaction with the switch process and knowledge about the new medication 4 to 8 weeks post-switch., Results: Sixty five patients completed the switch and 57 (88%) completed a follow-up survey. Most (86%) reported understanding why the switch was made, while 91% correctly identified that TAF is associated with reduced renal toxicity, and 73% correctly identified that TAF is associated with reduced bone toxicity. No statistically significant difference was found in satisfaction with or understanding of why the medication switch was made when assessed by sex, age, race, or education, but there was a trend toward significance in the distribution of answers based on education level with those with a high school diploma, General Educational Development (GED) or less being more likely to be satisfied with the medication switch (p = 0.074)., Conclusions: Education from an ambulatory clinic-based HIV pharmacist resulted in high rates of patient satisfaction and understanding of the switch from TDF to TAF-containing ART.

Combination antiretroviral therapies have revolutionized the treatment of HIV infection, and many patients now enjoy a lifespan equal to that of the general population. However, HIV-associated neurocognitive disorders (HAND) remain a major health concern, with between 30% and 70% of all HIV-infected patients developing cognitive impairments during their life time. One important feature of HAND is visuo-perceptual deficits, but the systems-level neural dynamics underlying these impairments are poorly understood. In the current study, we use magnetoencephalography and advanced time series analyses to examine these neural dynamics during a visuospatial processing task in a group of HIV-infected patients without HAND (n = 25), patients with HAND (n = 18), and a group of demographically-matched uninfected controls (n = 24). All participants completed a thorough neuropsychological assessment, and underwent magnetoencephalography and structural MRI protocols. In agreement with previous studies, patients with HAND performed significantly worse than HIV-infected patients without HAND and controls on the cognitive task, in terms of increased reaction time and decreased accuracy. Our magnetoencephalography results demonstrated that both spontaneous and neural oscillatory activity within the occipital cortices were affected by HIV infection, and that these patterns predicted behavioural performance (i.e. accuracy) on the task. Specifically, spontaneous neural activity in the alpha (8-16 Hz) and gamma (52-70 Hz) bands during the prestimulus baseline period, as well as oscillatory theta responses (4-8 Hz) during task performance were aberrant in HIV-infected patients, with both spontaneous alpha and oscillatory theta activity significantly predicting accuracy on the task and neuropsychological performance outside of the magnetoencephalography scanner. Importantly, these rhythmic patterns of population-level neural activity also distinguished patients by HAND status, such that spontaneous alpha activity in patients with HAND was elevated relative to HIV-infected patients without HAND and controls. In contrast, HIV-infected patients with and without HAND had increased spontaneous gamma compared to controls. Finally, there was a stepwise decrease in oscillatory theta activity as a function of disease severity, such that the response diminished from controls to patients without HAND to patients with HAND. Interestingly, the strength of the relationship between this theta response and accuracy also dissociated patient groups in a similar manner (controls > HIV with no HAND > HIV with HAND), indicating a reduced coupling between neurophysiology and behaviour in HIV-infected patients. This study provides the first neuroimaging evidence of a dissociation between HIV-infected patients with and without HAND, and these findings shed new light on the neural bases of cognitive impairment in HIV infection.

People with HIV infection with latent tuberculosis (TB) infection (LTBI) are at a 10-fold greater risk of developing active disease. Interferon gamma release assays and tuberculin skin testing have approximately 65% to 70% specificity for diagnosing LTBI in HIV-infected patients. LTBI can be successfully treated with isoniazid preventive therapy and early antiretroviral therapy (ART). Rapid molecular diagnostics have approximately 88% sensitivity and 98% specificity for identifying active TB. ART should be started early in patients with TB. A number of ART regimens are recommended in co-treatment that minimize the risk of drug-drug interactions. Although progress has been made, better diagnostics and TB regimens with lower risks of drug-drug interactions and shorter treatment durations are still needed. This article summarizes a presentation by Susan Swindells, MBBS, at the Ryan White HIV/AIDS Program Clinical Care Conference held in San Antonio in August 2017.

Objectives: The aim of the study was to compare the intraindividual plasma and intracellular peripheral blood mononuclear cell (PBMC) pharmacokinetics of tenofovir (TFV) and its intracellular metabolite, TFV-diphosphate (TFV-DP) in patients switched from a fixed-dose combination (FDC) tablet of TFV disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir (EVG)/cobicistat (COBI) to a FDC containing TFV alafenamide (TAF)/FTC/EVG/COBI., Design: A single-arm, prospective, nonrandomized, cross-over, pharmacokinetic study in patients receiving a TDF-containing regimen (TDF 300 mg/FTC 200 mg/EVG 150 mg/COBI 150 mg) switched to a TAF-containing FDC regimen (TAF 10 mg/FTC 200 mg/EVG 150 mg/COBI 150 mg)., Methods: Single, sparse plasma and PBMC samples were collected during TDF therapy and 4-8 weeks post-switch to the TAF-containing regimen. Plasma TFV and cell associated TFV-DP concentrations were determined with validated liquid chromatography tandem mass spectrometry methods. PBMC cell enumeration was performed by quantification of RNaseP (RPP30) gene copy numbers using a highly sensitive droplet digital PCR assay. Plasma and PBMC pharmacokinetics were summarized as geometric mean and compared as a geometric mean ratio with a Wilcoxon signed-rank test., Results: In 30 participants with evaluable data, TFV plasma concentrations decreased 90% [TDF: 99.98 (2.24) ng/ml vs. TAF: 10.2 (1.6) ng/ml, P < 0.001] after the switch while cell-associated TFV-DP increased 2.41-fold [TAF: 834.7 (2.49) vs. TDF: 346.85 (3.75) fmol/10 cells, P = 0.004]., Conclusion: Intraindividually, plasma TFV concentrations significantly decreased while cell associated TFV-DP concentrations significantly increased after switching from a TDF to a TAF-containing antiretroviral therapy regimen.

Background: The introduction of the Affordable Care Act (ACA) has provided unprecedented opportunities for uninsured people with HIV infection to access health insurance, and to examine the impact of this change in access. AIDS Drug Assistance Programs (ADAPs) have been directed to pursue uninsured individuals to enroll in the ACA as both a cost-saving strategy and to increase patient access to care. We evaluated the impact of ADAP-facilitated health insurance enrollment on health outcomes, and demographic and clinical factors that influenced whether or not eligible patients enrolled., Methods: During the inaugural open enrollment period for the ACA, 284 Nebraska ADAP recipients were offered insurance enrollment; 139 enrolled and 145 did not. Comparisons were conducted and multivariate models were developed considering factors associated with enrollment and differences between the insured and uninsured groups., Results: Insurance enrollment was associated with improved health outcomes after controlling for other variables, and included a significant association with undetectable viremia, a key indicator of treatment success (p < .0001). We found that minority populations and unstably housed individuals were at increased risk to not enroll in insurance., Conclusion: The National HIV/AIDS Strategy calls for new interventions to improve HIV health outcomes for disproportionately impacted populations. This study provides evidence to prioritize future ADAP-facilitated insurance enrollment strategies to reach minority populations and unstably housed individuals.

Impairments in working memory are among the most prevalent features of HIV-associated neurocognitive disorders (HAND), yet their origins are unknown, with some studies arguing that encoding operations are disturbed and others supporting deficits in memory maintenance. The current investigation directly addresses this issue by using a dynamic mapping approach to identify when and where processing in working memory circuits degrades. HIV-infected older adults and a demographically-matched group of uninfected controls performed a verbal working memory task during magnetoencephalography (MEG). Significant oscillatory neural responses were imaged using a beamforming approach to illuminate the spatiotemporal dynamics of neuronal activity. HIV-infected patients were significantly less accurate on the working memory task and their neuronal dynamics indicated that encoding operations were preserved, while memory maintenance processes were abnormal. Specifically, no group differences were detected during the encoding period, yet dysfunction in occipital, fronto-temporal, hippocampal, and cerebellar cortices emerged during memory maintenance. In addition, task performance in the controls covaried with occipital alpha synchronization and activity in right prefrontal cortices. In conclusion, working memory impairments are common and significantly impact the daily functioning and independence of HIV-infected patients. These impairments likely reflect deficits in the maintenance of memory representations, not failures to adequately encode stimuli., Competing Interests: Drs. Wilson, Heinrichs-Graham and Fox report no disclosures. Ms. Proskovec and Ms. O’Neill report no disclosures. Dr. Robertson serves as a consultant for Abbott and GlaxoSmithKline. Dr. Swindells reports receiving grant support to the University of Nebraska Medical Center from GlaxoSmithKline, Merck, and Pfizer for research unrelated to this study.

Background: Pharmacokinetics (PK) and pharmacodynamics of efavirenz and its 8-hydroxy metabolite (8-OH-efavirenz) have not been robustly evaluated in older HIV-infected persons., Objectives: We investigated relationships between neuropsychological (NP) performance and efavirenz and 8-OH-efavirenz PK in HIV-infected individuals >50 years of age., Methods: A cross-sectional study of HIV-infected adults on an efavirenz-containing regimen. The 12 and 18 h post-dose plasma efavirenz and 8-OH-efavirenz were quantified. CYP2B6 polymorphisms were investigated. Participants underwent neuropsychological tests; surveys were used for depression, sleep quality and anxiety. We investigated potential correlations of efavirenz and 8-OH-efavirenz plasma concentrations with NP performance, sleep, depression, anxiety and CYP2B6 polymorphisms., Results: Thirty participants (24 men and 6 women) with mean age 57 years (range 50-68). Plasma efavirenz concentrations did not correlate with NP performance; however, higher plasma 8-OH-efavirenz correlated with better learning (P = 0.002), language (P = 0.002) and total NP z-scores (P = 0.003). No correlation was seen for efavirenz or 8-OH-efavirenz with sleep, anxiety or depression. Median 12 and 18 h efavirenz plasma concentrations were 1967 ng/mL (IQR 1476-2394) and 1676 ng/mL (IQR 1120-2062), respectively. Median 12 and 18 h 8-OH-efavirenz plasma concentrations were 378 ng/mL (IQR 223-589) and 384 ng/mL (IQR 216-621), respectively. CYP2B6 G516T was associated with significantly higher plasma efavirenz at 12 and 18 h (P = 0.02) but not worse NP function., Conclusions: Better neurocognitive functioning was associated with higher 8-OH-efavirenz but not efavirenz plasma concentrations. No correlation was observed with sleep or depression. These findings point to a need for greater understanding of the metabolic profile of efavirenz and 8-OH-efavirenz in plasma and the CNS and relationships with antiviral effect and neurotoxicity., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Tuberculosis (TB) has been a leading cause of death for more than a century. While effective therapies exist, treatment is long and cumbersome. TB control is complicated by the overlapping problems created by global inadequacy of public health infrastructures, the interaction of the TB and human immunodeficiency virus (HIV) epidemics, and the emergence of drug-resistant TB. After a long period of neglect, there is now significant progress in the development of novel treatment regimens for TB. Focusing on treatment for active disease, we review pathways to TB regimen development and the new and repurposed anti-TB agents in clinical development., Competing Interests: The authors declare that they have no competing interests. No competing interests were disclosed. No competing interests were disclosed.

Background: An interim analysis of data from the HIV Prevention Trials Network (HPTN) 052 trial showed that antiretroviral therapy (ART) prevented more than 96% of genetically linked infections caused by human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. ART was then offered to all patients with HIV-1 infection (index participants). The study included more than 5 years of follow-up to assess the durability of such therapy for the prevention of HIV-1 transmission., Methods: We randomly assigned 1763 index participants to receive either early or delayed ART. In the early-ART group, 886 participants started therapy at enrollment (CD4+ count, 350 to 550 cells per cubic millimeter). In the delayed-ART group, 877 participants started therapy after two consecutive CD4+ counts fell below 250 cells per cubic millimeter or if an illness indicative of the acquired immunodeficiency syndrome (i.e., an AIDS-defining illness) developed. The primary study end point was the diagnosis of genetically linked HIV-1 infection in the previously HIV-1-negative partner in an intention-to-treat analysis., Results: Index participants were followed for 10,031 person-years; partners were followed for 8509 person-years. Among partners, 78 HIV-1 infections were observed during the trial (annual incidence, 0.9%; 95% confidence interval [CI], 0.7 to 1.1). Viral-linkage status was determined for 72 (92%) of the partner infections. Of these infections, 46 were linked (3 in the early-ART group and 43 in the delayed-ART group; incidence, 0.5%; 95% CI, 0.4 to 0.7) and 26 were unlinked (14 in the early-ART group and 12 in the delayed-ART group; incidence, 0.3%; 95% CI, 0.2 to 0.4). Early ART was associated with a 93% lower risk of linked partner infection than was delayed ART (hazard ratio, 0.07; 95% CI, 0.02 to 0.22). No linked infections were observed when HIV-1 infection was stably suppressed by ART in the index participant., Conclusions: The early initiation of ART led to a sustained decrease in genetically linked HIV-1 infections in sexual partners. (Funded by the National Institute of Allergy and Infectious Diseases; HPTN 052 ClinicalTrials.gov number, NCT00074581 .).

Background: Health care associated transmission of Mycobacterium tuberculosis (TB) is well described. A previous survey of infection control (IC) practices at clinical research sites in low and middle income countries (LMIC) funded by the National Institute of Allergy and Infectious Diseases (NIAID) conducting HIV research identified issues with respiratory IC practices. A guideline for TB IC based on international recommendations was developed and promulgated. This paper reports on adherence to the guideline at sites conducting or planning to conduct TB studies with the intention of supporting improvement., Methods: A survey was developed that assessed IC activities in three domains: facility level measures, administrative control measures and environmental measures. An external site monitor visited each site in 2013-2014, to complete the audit. A central review committee evaluated the site-level survey and results were tabulated. Fisher's exact test was performed to determine whether there were significant differences in practices at sites that had IC officers versus sites that did not have IC officers. Significance was assessed at p

Background: The Xpert MTB/RIF (Xpert) assay is a rapid nucleic acid amplification test widely used in settings of high tuberculosis prevalence to detect tuberculosis as well asrpoBmutations associated with rifampin resistance. Data are needed on the diagnostic performance of Xpert in lower-prevalence settings to inform appropriate use for both tuberculosis detection and the need for respiratory isolation., Methods: Xpert was compared to 2 sputum samples, each evaluated with acid-fast bacilli (AFB) smear and mycobacterial culture using liquid and solid culture media, from participants with suspected pulmonary tuberculosis from the United States, Brazil, and South Africa., Results: Of 992 participants enrolled with evaluable results, 22% had culture-confirmed tuberculosis. In 638 (64%) US participants, 1 Xpert result demonstrated sensitivity of 85.2% (96.7% in participants with AFB smear-positive [AFB(+)] sputum, 59.3% with AFB smear-negative [AFB(-)] sputum), specificity of 99.2%, negative predictive value (NPV) of 97.6%, and positive predictive value of 94.9%. Results did not differ between higher- and low-prevalence settings. A second Xpert assay increased overall sensitivity to 91.1% (100% if AFB(+), 71.4% if AFB(-)), with specificity of 98.9%. In US participants, a single negative Xpert result predicted the absence of AFB(+)/culture-positive tuberculosis with an NPV of 99.7%; NPV of 2 Xpert assays was 100%, suggesting a role in removing patients from airborne infection isolation. Xpert detected tuberculosis DNA and mutations associated with rifampin resistance in 5 of 7 participants with rifampin-resistant, culture-positive tuberculosis. Specificity for rifampin resistance was 99.5% and NPV was 98.9%., Conclusions: In the United States, Xpert testing performed comparably to 2 higher-tuberculosis-prevalence settings. These data support the use of Xpert in the initial evaluation of tuberculosis suspects and in algorithms assessing need for respiratory isolation., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

HIV-infected individuals are living longer on antiretroviral therapy, but many patients display signs that in some ways resemble premature aging. To investigate and quantify the impact of chronic HIV infection on aging, we report a global analysis of the whole-blood DNA methylomes of 137 HIV+ individuals under sustained therapy along with 44 matched HIV- individuals. First, we develop and validate epigenetic models of aging that are independent of blood cell composition. Using these models, we find that both chronic and recent HIV infection lead to an average aging advancement of 4.9 years, increasing expected mortality risk by 19%. In addition, sustained infection results in global deregulation of the methylome across >80,000 CpGs and specific hypomethylation of the region encoding the human leukocyte antigen locus (HLA). We find that decreased HLA methylation is predictive of lower CD4 / CD8 T cell ratio, linking molecular aging, epigenetic regulation, and disease progression., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01B&#95;2 group, N = 64) or 3 (F4/AS01B&#95;3 group, N = 62) doses of F4/AS01B or placebo (control group, N = 64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4 T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01B&#95;2 and control group (0.073 log10 copies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01B&#95;3 and control group (-0.096 log10 copies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4 T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01B recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01B&#95;2 group: angioedema). F4/AS01B induced polyfunctional F4-specific CD4 T-cells, but had no significant impact on F4-specific CD8 T-cell and anti-F4 antibody levels.F4/AS01B had a clinically acceptable safety profile, induced F4-specific CD4 T-cell responses, but did not reduce HIV-1 VL, impact CD4 T-cells count, delay ART initiation, or prevent HIV-1 related clinical events.

Background: Concomitant use of rifamycins to treat or prevent tuberculosis can result in subtherapeutic concentrations of antiretroviral drugs. We studied the interaction of efavirenz with daily rifapentine and isoniazid in human immunodeficiency virus (HIV)-infected individuals receiving a 4-week regimen to prevent tuberculosis., Methods: Participants receiving daily rifapentine and isoniazid with efavirenz had pharmacokinetic evaluations at baseline and weeks 2 and 4 of concomitant therapy. Efavirenz apparent oral clearance was estimated and the geometric mean ratio (GMR) of values before and during rifapentine and isoniazid was calculated. HIV type 1 (HIV-1) RNA was measured at baseline and week 8., Results: Eighty-seven participants were evaluable: 54% were female, and the median age was 35 years (interquartile range [IQR], 29-44 years). Numbers of participants with efavirenz concentrations ≥1 mg/L were 85 (98%) at week 0; 81 (93%) at week 2; 78 (90%) at week 4; and 75 (86%) at weeks 2 and 4. Median efavirenz apparent oral clearance was 9.3 L/hour (IQR, 6.42-13.22 L/hour) at baseline and 9.8 L/hour (IQR, 7.04-15.59 L/hour) during rifapentine/isoniazid treatment (GMR, 1.04 [90% confidence interval, .97-1.13]). Seventy-nine of 85 (93%) participants had undetectable HIV-1 RNA (<40 copies/mL) at entry; 71 of 75 (95%) participants had undetectable HIV-1 RNA at week 8. Two participants with undetectable HIV-1 RNA at study entry were detectable (43 and 47 copies/mL) at week 8., Conclusions: The proportion of participants with midinterval efavirenz concentrations ≥1 mg/L did not cross below the prespecified threshold of >80%, and virologic suppression was maintained. Four weeks of daily rifapentine plus isoniazid can be coadministered with efavirenz without clinically meaningful reductions in efavirenz mid-dosing concentrations or virologic suppression., Clinical Trials Registration: NCT 01404312., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We evaluated patient knowledge, attitudes, and beliefs regarding changes present with the Affordable Care Act (ACA). HIV-infected adults attending an academic medical center HIV clinic in Omaha, Nebraska were asked to complete a self-administered survey between November 2013 and March 2014. Information collected included demographics, knowledge regarding healthcare reform policies, as well as attitudes and beliefs regarding the potential impact of the ACA on patient access to healthcare. Basic descriptive statistics were used to assess demographic characteristics of respondents and outcomes of interest. Chi-square tests were used for comparisons of interest among participants; some trends were evaluated with Cochran-Armitage trend tests. Four hundred and six patients completed the questionnaire. Of the respondents 90% were between the ages of 27 and 64, 61% were white, 27% had no health insurance, and 21% reported that they felt they had or will eventually benefit from the ACA. The proportion who responded "I don't know" to this question decreased over the study period (p=0.036). Overall, 57% reported they do not believe that they are informed enough to make decisions about the ACA. In answering four knowledge-based questions, only 3% answered all of them correctly. Knowledge about the ACA was significantly associated with perception of benefit (p=0.018). HIV-infected patients are not well informed about the ACA and few perceive that they will benefit from healthcare reform. Targeted education and outreach are necessary to reduce the knowledge gap for this population that stands to benefit greatly from the ACA.

Combination antiretroviral therapy transformed human immunodeficiency virus (HIV)-infection from a terminal illness to a manageable condition, but these patients remain at a significantly elevated risk of developing cognitive impairments and the mechanisms are not understood. Some previous neuroimaging studies have found hyperactivation in frontoparietal networks of HIV-infected patients, whereas others reported aberrations restricted to sensory cortices. In this study, we utilize high-resolution structural and neurophysiological imaging to determine whether alterations in brain structure, function, or both contribute to HIV-related cognitive impairments. HIV-infected adults and individually matched controls completed 3-Tesla structural magnetic resonance imaging (sMRI) and a mechanoreception task during magnetoencephalography (MEG). MEG data were examined using advanced beamforming methods, and sMRI data were analyzed using the latest voxel-based morphometry methods with DARTEL. We found significantly reduced theta responses in the postcentral gyrus and increased alpha activity in the prefrontal cortices of HIV-infected patients compared with controls. Patients also had reduced gray matter volume in the postcentral gyrus, parahippocampal gyrus, and other regions. Importantly, reduced gray matter volume in the left postcentral gyrus was spatially coincident with abnormal MEG responses in HIV-infected patients. Finally, left prefrontal and postcentral gyrus activity was correlated with neuropsychological performance and, when used in conjunction, these two MEG findings had a sensitivity and specificity of over 87.5% for HIV-associated cognitive impairment. This study is the first to demonstrate abnormally increased activity in association cortices with simultaneously decreased activity in sensory areas. These MEG findings had excellent sensitivity and specificity for HIV-associated cognitive impairment, and may hold promise as a potential disease marker., (© 2014 Wiley Periodicals, Inc.)

Background: We evaluated predictors and outcomes of Mycobacterium tuberculosis bacteremia among participants undergoing baseline mycobacterial blood culture in the ACTG A5221 STRIDE study, a randomized clinical trial comparing earlier with later ART among HIV-infected patients suspected of having tuberculosis with CD4-positive T-lymphocyte counts (CD4 counts) <250 cells/mm(3). We conducted a secondary analysis comparing participants with respect to presence or absence of M. tuberculosis bacteremia., Methods: Participants with a baseline mycobacterial blood culture were compared with respect to the presence or absence of M. tuberculosis bacteremia. Baseline predictors of M. tuberculosis bacteremia were identified and participant outcomes were compared by mycobacteremia status., Results: Of 90 participants with baseline mycobacterial blood cultures, 29 (32.2%) were female, the median (IQR) age was 37 (31-45) years, CD4 count was 81 (33-131) cells/mm(3), HIV-1 RNA level was 5.39 (4.96-5.83) log10 copies/mL, and 18 (20.0%) had blood cultures positive for M. tuberculosis. In multivariable analysis, lower CD4 count (OR 0.85 per 10-cell increase, p = 0.012), hemoglobin ≤8.5 g/dL (OR 5.8, p = 0.049), and confirmed tuberculosis (OR 17.4, p = 0.001) were associated with M. tuberculosis bacteremia. There were no significant differences in survival and AIDS-free survival, occurrence of tuberculosis immune reconstitution inflammatory syndrome (IRIS), or treatment interruption or discontinuation by M. tuberculosis bacteremia status. IRIS did not differ significantly between groups despite trends toward more virologic suppression and greater CD4 count increases at week 48 in the bacteremic group., Conclusions: Among HIV-infected tuberculosis suspects, lower CD4 count, hemoglobin ≤8.5 g/dL, and the presence of microbiologically confirmed pulmonary tuberculosis were associated with increased adjusted odds of mycobacteremia. No evidence of an association between M. tuberculosis bacteremia and the increased risk of IRIS was detected., Trial Registration: ClinicalTrials.gov: NCT00108862 .

Background: Previous review of admissions from 2009-2011 in our institution found a 35.1% error rate in antiretroviral (ART) prescribing, with 55% of errors never corrected. Subsequently, our institution implemented a unified electronic medical record (EMR) and we developed a medication reconciliation process with an HIV pharmacist. We report the impact of the EMR on incidence of errors and of the pharmacist intervention on time to error correction., Methods: Prospective medical record review of HIV-infected patients hospitalized for >24 h between 9 March 2013 and 10 March 2014. An HIV pharmacist reconciled outpatient ART prescriptions with inpatient orders within 24 h of admission. Prescribing errors were classified and time to error correction recorded. Error rates and time to correction were compared to historical data using relative risks (RR) and logistic regression models., Results: 43 medication errors were identified in 31/186 admissions (16.7%). The incidence of errors decreased significantly after EMR (RR 0.47, 95% CI 0.34, 0.67). Logistic regression adjusting for gender and race/ethnicity found that errors were 61% less likely to occur using the EMR (95% CI 40%, 75%; P<0.001). All identified errors were corrected, 65% within 24 h and 81.4% within 48 h. Compared to historical data where only 31% of errors were corrected in <24 h and 55% were never corrected, errors were 9.4× more likely to be corrected within 24 h with HIV pharmacist intervention (P<0.001)., Conclusions: Use of an EMR decreased the error rate by more than 50% but despite this, ART errors remained common. HIV pharmacist intervention was key to timely error correction.

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 naïve 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.

Rationale and Objectives: Earlier initiation of antiretroviral therapy (ART) in HIV-tuberculosis (TB) is associated with increased immune reconstitution inflammatory syndrome (IRIS). The severity, frequency, and complications of TB IRIS were evaluated in A5221, a randomized trial of earlier ART (within 2 weeks after TB treatment initiation) vs. later ART (8-12 weeks after TB treatment) in HIV-infected patients starting TB treatment., Methods and Measurements: In 806 participants, TB IRIS was defined using published clinical criteria. Cases were classified as severe (hospitalization/death), moderate (corticosteroid use/invasive procedure), or mild (no hospitalization/procedures/steroids). Fisher exact, Wilcoxon, and log-rank tests were used for comparisons., Main Results: TB IRIS occurred in 61 (7.6%) patients: 10.4% in earlier vs. 4.7% in later ART, 11.5% with CD4 <50 vs. 5.4% with CD4 ≥50 cells per cubic millimeter. The CD4/ART arm interaction was significant, P = 0.014, with 44.3% of TB IRIS occurring with CD4 <50 and earlier ART. TB IRIS occurred sooner with earlier vs. later ART initiation, at a median of 29 vs. 82 days after TB treatment initiation (P < 0.001). IRIS manifestations included lymphadenopathy (59.0%), constitutional symptoms (54.1%), and radiographic changes (41.0%); central nervous system TB IRIS was uncommon (6.6%). TB IRIS was mild in 27.9%, moderate in 41.0%, and severe in 31.1%. No TB IRIS-associated deaths occurred. IRIS management required ≥1 invasive procedures in 34.4%, hospitalization in 31.1%, and corticosteroids in 54.1%., Conclusions: TB IRIS was more frequent with earlier ART initiation and CD4 <50 cells per cubic millimeter. As ART is implemented earlier in HIV-TB coinfection, programs will require the diagnostic capabilities, clinical resources, and training necessary to manage TB IRIS.

Background: Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes., Methods: The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581., Findings: 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group., Interpretation: Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment., Funding: US National Institute of Allergy and Infectious Diseases., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Limited performance data from line probe assays (LPAs), nucleic acid tests used for the rapid diagnosis of tuberculosis (TB), nontuberculosis mycobacteria (NTM), and Mycobacterium tuberculosis drug resistance are available for HIV-infected individuals, in whom paucibacillary TB is common. In this study, the strategy of testing sputum with GenoType MTBDRplus (MTBDR-Plus) and GenoType Direct LPA (Direct LPA) was compared to a gold standard of one mycobacterial growth indicator tube (MGIT) liquid culture. HIV-positive (HIV(+)) individuals with suspected TB from southern Africa and South America with <7 days of TB treatment had 1 sputum specimen tested with Direct LPA, MTBDR-Plus LPA, smear microscopy, MGIT, biochemical identification of mycobacterial species, and culture-based drug-susceptibility testing (DST). Of 639 participants, 59.3% were MGIT M. tuberculosis culture positive, of which 276 (72.8%) were acid-fast bacillus (AFB) smear positive. MTBDR-Plus had a sensitivity of 81.0% and a specificity of 100%, with sensitivities of 44.1% in AFB smear-negative versus 94.6% in AFB smear-positive specimens. For specimens that were positive for M. tuberculosis by MTBDR-Plus, the sensitivity and specificity for rifampin resistance were 91.7% and 96.6%, respectively, and for isoniazid (INH) they were 70.6% and 99.1%. The Direct LPA had a sensitivity of 88.4% and a specificity of 94.6% for M. tuberculosis detection, with a sensitivity of 72.5% in smear-negative specimens. Ten of 639 MGIT cultures grew Mycobacterium avium complex or Mycobacterium kansasii, half of which were detected by Direct LPA. Both LPA assays performed well in specimens from HIV-infected individuals, including in AFB smear-negative specimens, with 72.5% sensitivity for M. tuberculosis identification with the Direct LPA and 44.1% sensitivity with MTBDR-Plus. LPAs have a continued role for use in settings where rapid identification of INH resistance and clinically relevant NTM are priorities.

A blood collection tube (Cyto-Chex(®) BCT), which can stabilize white blood cells and immunogenic markers in blood samples, was investigated for its ability to inactivate human immunodeficiency virus (HIV) and stabilize HIV for viral load quantitation. Laboratory-adapted HIV strains were either treated or untreated with the stabilizing reagent present in Cyto-Chex(®) BCT. A dilution of the reagent used to treat virus was 1:66, which was similar to the reagent concentration in Cyto-Chex(®) BCT device when blood was drawn into it. In another experiment, blood was drawn from HIV patients into one acid citrate dextrose (ACD) tube and one Cyto-Chex(®) BCT. At indicated time points, aliquots were taken of treated and untreated viral dilutions and from plasma of HIV-positive patient blood samples and analyzed using reverse transcriptase and TZM-bl cell assays to determine HIV inactivation. In laboratory-adapted HIV strains and HIV-positive patient plasma, HIV was completely inactivated within 2 and 3h of contact with a 1:66 dilution of Cyto-Chex reagent, respectively. Samples from HIV-positive patient plasma showed that viral load was stable in Cyto-Chex(®) BCT for 7 days at room temperature. Therefore, it is concluded that the chemical reagent present in the Cyto-Chex(®) BCT blood collection device is capable of complete inhibition of HIV infectivity in blood samples within 3h and stabilizing the viral load for 7 days at room temperature., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Errors in prescribing antiretroviral therapy (ART) often occur with the hospitalization of HIV-infected patients. The rapid identification and prevention of errors may reduce patient harm and healthcare-associated costs., Methods: A retrospective review of hospitalized HIV-infected patients was carried out between 1 January 2009 and 31 December 2011. Errors were documented as omission, underdose, overdose, duplicate therapy, incorrect scheduling and/or incorrect therapy. The time to error correction was recorded. Relative risks (RRs) were computed to evaluate patient characteristics and error rates., Results: A total of 289 medication errors were identified in 146/416 admissions (35%). The most common was drug omission (69%). At an error rate of 31%, nucleoside reverse transcriptase inhibitors were associated with an increased risk of error when compared with protease inhibitors (RR 1.32; 95% CI 1.04-1.69) and co-formulated drugs (RR 1.59; 95% CI 1.19-2.09). Of the errors, 31% were corrected within the first 24 h, but over half (55%) were never remedied. Admissions with an omission error were 7.4 times more likely to have all errors corrected within 24 h than were admissions without an omission. Drug interactions with ART were detected on 51 occasions. For the study population (n = 177), an increased risk of admission error was observed for black (43%) compared with white (28%) individuals (RR 1.53; 95% CI 1.16-2.03) but no significant differences were observed between white patients and other minorities or between men and women., Conclusion: Errors in inpatient ART were common, and the majority were never detected. The most common errors involved omission of medication, and nucleoside reverse transcriptase inhibitors had the highest rate of prescribing error. Interventions to prevent and correct errors are urgently needed.

The introduction of combination antiretroviral therapy significantly reduced the prevalence of the most severe form of HIV-associated neurocognitive disorders (HAND). Despite this decline, 35-70 % of HIV-infected patients continue to develop mild motor and cognitive impairments. Although neuropsychological studies have shown that HAND affects a wide array of cognitive functions, a formal diagnosis is still based on the exclusion of opportunistic infections and other common ailments, as no specific tests or biomarkers are currently available. In this study, we used magnetoencephalography (MEG) to measure neural activity during the resting-state in 15 HIV-infected older patients and a demographically matched group of 15 uninfected controls. MEG is a noninvasive and direct measure of neural activity with excellent spatiotemporal resolution. All MEG data were coregistered to structural magnetic resonance images, corrected for head motion, fitted to a regional-level source model, and subjected to spectral analyses to quantify population-level neural oscillatory activity. We found that HIV-infected persons exhibited decreased beta oscillations in the supplementary motor area bilaterally, paracentral lobule, posterior cingulate, and bilateral regions of the superior parietal lobule relative to healthy controls. Beta oscillations in the posterior cingulate, a critical component of the default mode network, were also positively correlated with patient scores on the memory recall aspect of the Hopkins Verbal Learning Test-Revised. These results demonstrate that chronic HIV infection does not uniformly disturb cortical function, and that neuronal populations in dorsomedial motor and parietal cortices are especially affected. These findings also suggest that resting-state MEG recordings may hold significant promise as a functional biomarker for identifying HAND and monitoring disease progression.

Aim: To gauge patient interest in receiving long-acting injectable nanoformulated antiretroviral therapy., Methods: Four hundred adult HIV-infected patients currently prescribed antiretroviral therapy were surveyed. χ(2) tests were used for comparisons of interest across groups., Results: Respondents were 68% male and 53% African-American, with a mean age of 47 years. Overall, 73% of patients indicated that they would definitely or probably try injectable nanoformulated antiretroviral therapy; 61% with weekly dosing; 72% every 2 weekly; and 84% monthly. In total, 48% indicated that they were very concerned about the possible side effects and 35% were very concerned about needle use., Conclusion: The majority of respondents indicated that they definitely or probably would try parenteral nanoformulated antiretroviral therapy.

Objective: To address the need for nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens, we explored the virologic and pharmacokinetic characteristics of maraviroc plus ritonavir-boosted darunavir in a single-arm, open-label, 96-week study., Methods: Twenty-four antiretroviral-naive R5 HIV-1-infected participants received maraviroc 150 mg and darunavir/ritonavir (DRV/r) 800/100 mg (MVC/DRV/r) once daily. The primary outcome was virologic failure (VF) = confirmed viral load (VL) >50 copies per milliliter at week 24 in the modified intent-to-treat population. To determine viral dynamics, participant-specific first- and second-phase empirical Bayes estimates were compared with decay rates from efavirenz (EFV) plus lopinavir/ritonavir, lopinavir/ritonavir plus 2NRTIs, and EFV plus 2NRTIs. Maraviroc plasma concentrations were determined at weeks 2, 4, 12, 24, and 48., Results: Baseline median (Q1, Q3) CD4 count and VL were 455 (299, 607) cells per cubic millimeter and 4.62 (4.18, 4.80) log10 copies per milliliter, respectively. VF occurred in 3 of 24 participants {12.5% [95% confidence interval (CI): 2.7 to 32.4]} at week 24. One of these resuppressed, yielding a week 48 VF rate of 2/24 [8.3% (95% CI: 1.0 to 27.0)]. The week 48 failures were 2 of the 4 participants (50%) with baseline VL >100,000 copies per milliliter. Week 96 VF rate was 2/20 [10% (95% CI: 1.2 to 31.7)]. Phase 1 decay was faster with MVC/DRV/r than reported for ritonavir-boosted lopinavir plus 2NRTIs (P = 0.0063) and similar to EFV-based regimens. Individual maraviroc trough concentrations collected between 20 and 28 hours post dose (n = 59) was 13.7 to 130 ng/mL (Q1, 23.4 ng/mL; Q3, 46.5 ng/mL), and modeled steady-state concentration was 128 ng/mL., Conclusions: MVC/DRV/r 150/800/100 mg once daily has potential for treatment-naive patients with R5 HIV-1.

Despite the availability of combination antiretroviral therapy, at least mild cognitive dysfunction is commonly observed in HIV-infected patients, with an estimated prevalence of 35-70 %. Neuropsychological studies of these HIV-associated neurocognitive disorders (HAND) have documented aberrations across a broad range of functional domains, although the basic pathophysiology remains unresolved. Some of the most common findings have been deficits in fine motor control and reduced psychomotor speed, but to date no neuroimaging studies have evaluated basic motor control in HAND. In this study, we used magnetoencephalography (MEG) to evaluate the neurophysiological processes that underlie motor planning in older HIV-infected adults and a matched, uninfected control group. MEG is a noninvasive and direct measure of neural activity with good spatiotemporal precision. During the MEG recording, participants fixated on a central crosshair and performed a finger-tapping task with the dominant hand. All MEG data was corrected for head movements, preprocessed, and imaged in the time-frequency domain using beamforming methodology. All analyses focused on the pre-movement beta desynchronization, which is known to be an index of movement planning. Our results demonstrated that HIV-1-infected patients have deficient beta desynchronization relative to controls within the left/right precentral gyri, and the supplementary motor area. In contrast, HIV-infected persons showed abnormally strong beta responses compared to controls in the right dorsolateral prefrontal cortex and medial prefrontal areas. In addition, the amplitude of beta activity in the primary and supplementary motor areas correlated with scores on the Grooved Pegboard test in HIV-infected adults. These results demonstrate that primary motor and sensory regions may be particularly vulnerable to HIV-associated damage, and that prefrontal cortices may serve a compensatory role in maintaining motor performance levels in infected patients.

Background: Rifampin (RIF) upregulates CYP 450 isoenzymes, potentially lowering efavirenz (EFV) exposure. The US EFV package insert recommends an EFV dose increase for patients on RIF weighing ≥50 kg. We conducted a pharmacokinetic study to evaluate EFV trough concentrations (Cmin) and human immunodeficiency virus (HIV) virologic suppression in patients on EFV (600 mg) and RIF-based tuberculosis treatment in the multicenter randomized trial (ACTG A5221)., Methods: EFV Cmin was measured 20-28 hours post-EFV dose at weeks 4, 8, 16, 24 on-RIF and weeks 4, 8 off-RIF. Results were evaluated with 2-sided Wilcoxon rank-sum, χ(2), Fisher exact tests and logistic regression (5% type I error rate)., Results: Seven hundred eighty patients received EFV; 543 provided ≥1 EFV Cmin. Median weight was 52.8 kg (interquartile range [IQR], 48.0-59.5), body mass index 19.4 kg/m(2) (IQR, 17.5-21.6), and age 34 years (IQR, 29-41); 63% were male, 74% black. Median Cmin was 1.96 µg/mL on-RIF versus 1.80 off-RIF (P = .067). Cmin were significantly higher on-RIF versus off-RIF in blacks (2.08 vs 1.75, P = .005). Weight ≥60 kg on-RIF, compared to <60 kg, was associated with lower EFV Cmin (1.68 vs 2.02, P = .021). However, weight ≥60 kg was associated with more frequent HIV RNA < 400 copies/mL at week 48, compared to weight <60 kg (81.9% vs 73.8%, P = .023)., Conclusions: EFV and RIF-based tuberculosis therapy coadministration was associated with a trend toward higher, not lower, EFV Cmin compared to EFV alone. Patients weighing ≥60 kg had lower median EFV Cmin versus those <60 kg, but there was no association of higher weight with reduced virologic suppression. These data do not support weight-based dosing of EFV with RIF.

Objectives: Emerging data suggest that HIV disease and its treatment affect the aging process. Accurate and reliable measures of functional status are needed to investigate this further., Design: A pilot study in groups of younger and older HIV-infected adults using objective measures of function., Methods: Evaluations included neuropsychological testing, grip strength, balance assessed by the Wii Balance Board, and actigraphy. Surveys were used for depression, fatigue, loneliness, self-reported activity level, and sexual function. Two-samplet test or Wilcoxon rank sum tests were used for continuous variables and exact chi-square tests were used for comparison between groups., Results: Twenty-one participants were 20 to 40 years old (younger; mean age, 31.5), and 20 were more than 50 years old (older; mean age, 56.5). There was no difference between groups for depression, fatigue, or loneliness. Overall, there was a trend to lower scores in the older age group for neuropsychologicalz score (P = .11) and for verbal learning (P = .09). Functioning in the memory domain was significantly lower in older subjects (P = .007). There was no difference in executive function, speed of processing, memory, motor skills, or total activity. Gender differences in sexual function were observed. Four older and 3 younger participants met the definition of frailty. Total activity by actigraphy did not correlate well with self-reported activity., Conclusions: Objective tests were well accepted and feasible to perform, although not all are suitable for widespread clinical or research use. Objective measurements of activity did not correlate well with patient self-report, which has implications for future studies in this area.

Objective: Shortly after infection, HIV enters the brain and causes widespread inflammation and neuronal damage, which ultimately leads to neuropsychological impairments. Despite a large body of neuroscience and imaging studies, the pathophysiology of these HIV-associated neurocognitive disorders (HAND) remains unresolved. Previous neuroimaging studies have shown greater activation in HIV-infected patients during strenuous tasks in frontal and parietal cortices, and less activation in the primary sensory cortices during rest and sensory stimulation., Methods: High-density magnetoencephalography (MEG) was utilized to evaluate the basic neurophysiology underlying attentive, visual processing in older HIV-infected adults and a matched non-infected control group. Unlike other neuroimaging methods, MEG is a direct measure of neural activity that is not tied to brain metabolism or hemodynamic responses. During MEG, participants fixated on a centrally-presented crosshair while intermittent visual stimulation appeared in their top-right visual-field quadrant. All MEG data was imaged in the time-frequency domain using beamforming., Results: Uninfected controls had increased neuronal synchronization in the 6-12 Hz range within the right dorsolateral prefrontal cortex, right frontal eye-fields, and the posterior cingulate. Conversely, HIV-infected patients exhibited decreased synchrony in these same neural regions, and the magnitude of these decreases was correlated with neuropsychological performance in several cortical association regions., Conclusions: MEG-based imaging holds potential as a noninvasive biomarker for HIV-related neuronal dysfunction, and may help identify patients who have or may develop HAND. Reduced synchronization of neural populations in the association cortices was strongly linked to cognitive dysfunction, and likely reflects the impact of HIV on neuronal and neuropsychological health.

Paired plasma and intracellular samples were obtained from 12 HIV-infected adults taking raltegravir twice daily (b.i.d.), and after switching to once daily. With b.i.d. dosing, no plasma trough concentrations were below the IC95, in contrast to 33% for once daily dosing. Fifty percent of the once daily group had intracellular trough concentrations below the inhibitory concentration 95 (IC95), 25% in the b.i.d. group. Lower plasma and intracellular concentrations may contribute to inferior virologic suppression rates observed with once daily raltegravir dosing.

Objective: To determine the impact of missed visits on CD4 cell count with HIV disease in a Midwest clinic., Methods: This was a mixed method study consisting of a quantitative retrospective cohort study of missed clinic visits among HIV-infected patients, and a qualitative study to collect information on factors impacting appointment attendance. A drop in CD4 cell count greater than 50 cells/mm(3) from baseline was the primary outcome variable for the quantitative study. The exposure variable was missed visits., Results: Of 77 patients, 16.4% experienced the outcome of interest. Lower visit proportions increased the risk of a CD4 drop (hazard ratio 0.0188, 95% confidence interval 0.001-0.292). For each 10% increase in the missed visit proportion, the risk of a CD4 drop of >50 cells/mm(3) from baseline increased by 33%. Qualitative data suggested that stigma, external support, and physician-patient interactions impacted engagement in care., Conclusion: These results may help providers increase patient motivation and ability to attend clinic appointments., (Copyright © 2012 International Society for Infectious Diseases. All rights reserved.)

Standard tuberculosis (TB) treatment includes an initial regimen containing drugs that are both rapidly bactericidal (isoniazid) and sterilizing (rifampin and pyrazinamide), and ethambutol to help prevent the emergence of drug resistance. Antagonism between isoniazid and pyrazinamide has been demonstrated in a TB treatment mouse model. Because isoniazid's bactericidal activity is greatest during the initial two treatment days, we hypothesized that removing isoniazid after the second day would increase the effectiveness of the standard regimen. To test this hypothesis, we developed a mouse model to measure the early bactericidal activity (EBA) of drug regimens designed to analyze the essentiality of both isoniazid and pyrazinamide during the first 14 d of therapy. Our results clearly indicate that discontinuation of isoniazid after the second day of treatment increases the EBA of standard therapy in the mouse model, whereas omitting pyrazinamide during the first 14 d was detrimental. Substitution of moxifloxacin for isoniazid on day 3 did not increase the EBA compared with only removing isoniazid after day 2. Our data show that a mouse model can be used to analyze the EBA of TB drugs, and our findings support pursuing clinical trials to evaluate the possible benefit of removing isoniazid after the first 2 treatment days.

Background: We present a case of a patient who had development of uterine clostridial myonecrosis after elective thermal balloon endometrial ablation in the absence of identifiable risk factors., Case: A 51-year-old woman underwent uneventful thermal balloon endometrial ablation for the treatment of menorrhagia. The next day, she presented with acute inflammatory syndrome, severe intravascular hemolysis, and acute kidney injury. The blood cultures and the high vaginal swab showed moderate growth of Clostridium species. A total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. Her postoperative course was uneventful, and renal function gradually recovered., Conclusion: Clostridial myonecrosis after uncomplicated surgery, although rare, should be considered in the differential diagnosis of the acutely septic patient with massive hemolysis, regardless of the presence of patient's risk factors.

Combined antiretroviral therapy (ART) tremendously improved the lifespan and symptoms associated with AIDS-defining illness in affected individuals. However, chronic ART-treated patients frequently develop age-dependent complications, including dementia, diabetes, and hyperlipidemia: all risk factors of Alzheimer's disease. Importantly, the effect of ART compounds on amyloid generation and clearance has never been systematically examined. Nine prescribed HIV protease inhibitors were tested for their effect on amyloid-β peptide (Aβ) clearance in primary cultured human monocyte-derived macrophages. Atazanavir, ritonavir, and saquinavir modestly inhibited of Aβ degradation, while lopinavir, nelfinavir, and ritonavir enhanced secretion of undigested Aβ after phagocytosis. Lopinavir, nelfinavir, ritonavir, and saquinavir inhibited endogenous Aβ40 production from primary cultured human cortical neurons, which were associated with reduction in Beta-site APP Converting Enzyme 1 (BACE1) and γ-secretase enzyme activities. However, ART compounds showed little inhibition of purified BACE1 activity in vitro, suggesting the indirect effect of ART compounds on BACE1 activity in neurons. Finally, nefinavir or lopinavir/ritonavir (Kaletra) were orally administered for 30 days into APP SCID mice expressing a double mutant form of APP 695 (KM670/671NL + V717F) in homozygosity for the scid allele of Prkdc. There was no difference in beta-amyloidosis by ART drug administration as determined by both immunohistochemistry and ELISA measurements although the therapeutic doses of the ART compounds was present in the brain. These data demonstrated that ART drugs can inhibit Aβ clearance in macrophages and Aβ production in neurons, but these effects did not significantly alter Aβ accumulation in the mouse brain.

The development, evaluation, and implementation of new and improved diagnostics have been identified as critical needs by human immunodeficiency virus (HIV) and tuberculosis researchers and clinicians alike. These needs exist in international and domestic settings and in adult and pediatric populations. Experts in tuberculosis and HIV care, researchers, healthcare providers, public health experts, and industry representatives, as well as representatives of pertinent US federal agencies (Centers for Disease Control and Prevention, Food and Drug Administration, National Institutes of Health, United States Agency for International Development) assembled at a workshop proposed by the Diagnostics Working Group of the Federal Tuberculosis Taskforce to review the state of tuberculosis diagnostics development in adult and pediatric populations.

Background: Drug-drug interactions complicate management of coinfection with HIV-1 and Mycobacterium tuberculosis. Bedaquiline (formerly TMC207), an investigational agent for the treatment of tuberculosis, is metabolized by cytochrome P450 (CYP) 3A which may be induced by the antiretroviral drug efavirenz., Methods: This was a phase 1 pharmacokinetic drug interaction trial. Each healthy volunteer received two 400 mg doses of bedaquiline, the first alone and the second with concomitant steady-state efavirenz. Plasma pharmacokinetic sampling for bedaquiline and its N-monodesmethyl metabolite was performed over 14 days after each bedaquiline dose. Steady-state efavirenz pharmacokinetics were also determined. Efavirenz metabolizer status was based on CYP2B6 composite 516/983 genotype., Results: Thirty-three of 37 enrolled subjects completed the study. Geometric mean of ratios for bedaquiline with efavirenz versus bedaquiline alone were 0.82 [90% confidence interval (CI): 0.75 to 0.89] for the 14-day area under the concentration-time curve (AUC0-336 h) and 1.00 (90% CI: 0.88 to 1.13) for the maximum concentration (Cmax). For N-monodesmethyl metabolite, the geometric mean of ratios was 1.07 (90% CI: 0.97 to 1.19) for AUC0-336 h and 1.89 (90% CI: 1.66 to 2.15) for C(max). There were no grade 3 or 4 clinical adverse events. One subject developed asymptomatic grade 3 serum transaminase elevation, prompting study drug discontinuation. Efavirenz concentrations stratified by CYP2B6 genotype were similar to historical data., Conclusions: Single-dose bedaquiline was well tolerated alone and with steady-state efavirenz. The effect of efavirenz on bedaquiline concentrations is unlikely to be clinically significant.