Transcriptionally Active Defective HIV-1 Proviruses and Their Association With Immunological Nonresponse to Antiretroviral Therapy.

A subset of antiretroviral therapy-treated persons with human immunodeficiency virus (HIV), referred to as immunological nonresponders (INRs), fails to normalize CD4+ T-cell numbers. In a case-control study involving 26 INRs (CD4 < 250 cells/µL) and 25 immunological responders (IRs; CD4 ≥ 250 cells/µL), we evaluated the potential contribution of transcriptionally competent defective HIV-1 proviruses to poor CD4+ T-cell recovery. Compared to the responders, the INRs had higher levels of cell-associated HIV RNA (P = .034) and higher percentages of HLA-DR+ CD4+ T cells (P < .001). While not encoding replication-competent viruses, the RNA transcripts frequently encoded HIV-1 Gag-p17 and Nef proteins. These transcripts and/or resulting proteins may activate pathway(s) leading to the immunological nonresponse phenotype.

The Association of Air Pollution Exposure With Glucose and Lipid Levels: The Role of an Extreme Air Pollution Event Alongside 2 Decades of Moderate Exposure.

Extreme air pollution events and moderate exposure to fine particulate matter (PM2.5) are associated with increased cardiometabolic risk. The World Trade Center (WTC) Health Program general responder cohort includes responders to the WTC disaster. We investigated whether their exposure to this extreme air pollution event (2001) was associated with long-term metabolic outcomes, independently from the associations of intermediate-term PM2.5 exposure later in life (2004-2019). We included 22,447 cohort members with cholesterol (n = 96,155) and glucose (n = 81,599) laboratory results. Self-reported WTC exposure was derived from a questionnaire. PM2.5 exposure was derived from a satellite-based model. We observed an increase of 0.78 mg/dL (95% confidence interval (CI): 0.30, 1.26) in glucose and 0.67 mg/dL (95% CI: 1.00, 2.35) in cholesterol levels associated with an interquartile range increase in PM2.5 averaged 6 months before the study visit. Higher WTC-exposure categories were also associated with higher cholesterol (0.99 mg/dL, 95% CI: 0.30, 1.67, for intermediate exposure) and glucose (0.82 mg/dL, 95% CI: 0.22, 1.43, for high exposure) levels. Most associations were larger among people with diabetes. Extreme air pollution events and intermediate PM2.5 exposure have independent metabolic consequences. These exposures contributed to higher glucose and lipids levels among WTC responders, which may be translated into increased cardiovascular risk.

Disparities in place of death for patients with primary brain tumors and brain metastases in the USA.

PURPOSE: Patients with primary or metastatic brain tumors often require intensive end-of-life care, for which place of death may serve as a quality metric. Death at home or hospice is considered a more "ideal" location. Comprehensive information on place of death of people with brain tumors is lacking. METHODS: Using CDC Wonder Database data, those who died in the USA from a solid cancer from 2003 to 2016 were included and place of death for those with primary brain, brain metastases, and solid non-brain tumors were compared. Multivariate logistic regression tested for disparities in place of death. RESULTS: By 2016, 51.1% of patients with primary brain tumors and 45.2% with brain metastases died at home. 15.9% of patients with primary brain tumors and 23.6% with brain metastases died in the hospital. Black patients were least likely to die at home or hospice. For patients with primary brain tumors, being married (OR = 2.25 (95%CI 2.16-2.34), p < 0.01) and having an advanced degree (OR = 1.204 (95%CI 1.15-1.26), p < 0.01) increased odds of home/hospice death; older age (OR = 0.50 (95%CI 0.46-0.54), p < 0.01) decreased odds for home/hospice death. For patients with brain metastases, being married (OR = 2.19 (95%CI 2.11-2.26), p < 0.01) increased odds of home/hospice death and male sex (OR = 0.87 (095%CI .85-0.89), p < 0.01) and older age (OR = 0.59 (95%CI 0.47-0.75), p < 0.01) decreased odds of home/hospice death. CONCLUSION: Disparities exist in place of death in the brain tumor population. Focused interventions are indicated to increase the utilization of hospice in those with metastatic cancer, under-represented minority groups, and the elderly population.

Pre-term delivery and long-term risk of heart failure in women: a national cohort and co-sibling study.

AIMS: Women who deliver pre-term have higher future risks of hypertension and ischaemic heart disease, but long-term risks of heart failure (HF) are unknown. We examined these risks in a large national cohort. METHODS AND RESULTS: All 2 201 284 women with a singleton delivery in Sweden during 1973-2015 were followed up for inpatient or outpatient HF diagnoses through 2015. Cox regression was used to compute hazard ratios (HRs) for HF associated with pregnancy duration, adjusting for other maternal factors. Co-sibling analyses assessed for confounding by shared familial (genetic and/or environmental) factors. In 48.2 million person-years of follow-up, 19 922 women were diagnosed with HF (median age: 60.7 years). Within 10 years after delivery, the adjusted HR was 2.96 [95% confidence interval (CI): 2.48-3.53] for HF associated with pre-term (gestational age: <37 weeks) compared with full-term (39-41 weeks) delivery. Stratified HRs were 4.27 (2.54-7.17) for extremely pre-term (22-27 weeks), 3.39 (2.57-4.48) for moderately pre-term (28-33 weeks), 2.70 (2.19-3.32) for late pre-term (34-36 weeks), and 1.70 (1.45-1.98) for early term (37-38 weeks). These HRs declined but remained elevated at 10-19 years (pre-term vs. full term: HR: 2.19; 95% CI: 1.94-2.46), 20-29 years (1.80; 1.67-1.95), and 30-43 years (1.56; 1.47-1.66) after delivery, and were not explained by shared familial factors. CONCLUSION: Pre-term and early term delivery were associated with markedly increased future hazards for HF, which persisted after adjusting for other maternal and familial factors and remained elevated 40 years later. Pre-term and early-term delivery should be recognized as risk factors for HF across the life course. KEY QUESTION: What are the long-term hazards for heart failure (HF) across the life course in women who deliver preterm? KEY FINDING: Preterm and early term delivery were associated with ∼3- and 1.7-fold adjusted hazards for HF in the next 10 years vs. full-term delivery. These hazards declined but remained elevated 40 years later, and were not explained by shared familial factors. TAKE HOME MESSAGE: Preterm and early term delivery were associated with increased future hazards for HF, which persisted for 40 years after adjusting for other maternal and familial factors. Preterm and early term delivery should be recognized as lifelong risk factors for HF.

The Creation of a Program of Engagement and Outreach for COVID-19 Among African Americans Through Community-Academic Partnerships.

The COVID-19 pandemic has disproportionately affected racial and ethnic minority groups in the U.S. Over a 7-week period in late 2020, with funding from the NC Office of Minority Health and Health Disparities, the West Greenville Health Council (WGHC), a community-academic, non-profit partnership, engaged and activated a 27-member organizational partnership network for COVID-19 health communication and personal protective equipment (PPE) distribution in African American communities in Eastern North Carolina. Outreach included: local production and dissemination of 10 culturally relevant safety videos, 10 risk, prevention, and safety postcard messages, 3 virtual forums, and PPE kit distribution via the network and their distribution venues. Communication mediums included social media posts (i.e., Facebook and YouTube), network email distribution lists, and postcards distributed along with PPE kits. Outreach activities were evaluated via an online survey, reach of social media posts, and PPE distribution. Working through the organizational network, the WGHC reached a combined total of 30,310 community members with educational materials. Forty-four outreach events were held during this period and over 8000 PPE kits were distributed. The online survey, distributed through the network, yielded more than 400 completed questionnaires. This tool was used to gain insights on community perceptions of COVID-19 safety barriers and media messages. The activation of the network as an approach for rapid response to an emerging public health crisis greatly expanded the reach of the WGHC. The WGHC is working to institutionalize the network to address future emerging health threats, as well as the dissemination of health information more generally.

Metabolic Changes in Chronic Hepatitis C Patients Who Carry IFNL4-ΔG and Achieve Sustained Virologic Response With Direct-Acting Antiviral Therapy.

BACKGROUND: Clearance of hepatitis C virus (HCV) results in rapid changes in metabolic parameters early in direct-acting antiviral (DAA) therapy. Long-term changes after sustained virologic response (SVR) remain unknown. METHODS: We investigated longitudinal changes in metabolic and inflammatory outcomes in chronic hepatitis C (CHC) patients: low-density lipoprotein (LDL), high-density lipoprotein, triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) using a general linear model for repeated measurements at 5 clinical time points and by human immunodeficiency virus (HIV) coinfection and IFNL4 genotype. RESULTS: The mean LDL increased markedly during DAA therapy (pre-DAA, 86.6 to DAA, 107.4 mg/dL; P < .0001), but then it decreased to 97.7 mg/dL by post-SVR year 1 (P < .001 compared with DAA; P = .0013 compared with SVR). In patients who carry the IFNL4-ΔG allele, mean LDL increased during treatment, then decreased at post-SVR year 1; however, in patients with TT/TT, genotype did not change during and after DAA treatment. The mean ALT and AST normalized rapidly between pre-DAA and DAA, whereas only mean ALT continued to decrease until post-SVR. Metabolic and inflammatory outcomes were similar by HIV-coinfection status. CONCLUSIONS: Changes in LDL among CHC patients who achieved SVR differed by IFNL4 genotype, which implicates the interferon-λ4 protein in metabolic changes observed in HCV-infected patients.

Testosterone in Men With Chronic Hepatitis C Infection and After Hepatitis C Viral Clearance.

BACKGROUND: Hepatitis C virus (HCV) and hepatic dysfunction are associated with low total and free testosterone (TT and FT) and high sex hormone-binding globulin (SHBG). However, little is known about changes in testosterone following successful HCV treatment. METHODS: We evaluated testosterone levels and the prevalence of low testosterone in a cohort of 327 men with chronic HCV infection (human immunodeficiency virus [HIV] coinfection = 150) and in a subset of 85 men with testosterone levels obtained pre-HCV treatment and after sustained virologic response (SVR). Median follow-up was 36 months. RESULTS: Participants with active HCV at baseline had higher TT (P < .0001) and SHBG (P < .0001) compared with participants who had achieved SVR, whereas FT did not differ. Low TT (<10.4 nmol/L) was more prevalent in participants with SVR compared with active HCV (P = .002); however, low FT (<0.1735 nmol/L) was common (50% active HCV, 43% SVR) and did not different between groups. For participants with longitudinal determinations, TT and SHBG decreased significantly (P < .0001) while FT remained unchanged post-SVR. Low FT persisted after SVR (pre-treatment 58%, post-SVR 54%, P = .72). HIV status and change in aspartate aminotrasferase-to-platelet ratio were significant independent predictors of change in FT following SVR. CONCLUSIONS: During active HCV infection, testosterone deficiency may be masked due to elevated SHBG. Despite improvements in SHBG following SVR, low FT was common and persisted after HCV clearance, indicating the need for enhanced awareness and screening using estimates of FT following successful treatment of chronic HCV. CLINICAL TRIALS REGISTRATION: NCT01350648.

Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine.

Background: Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication. Methods: This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points. Results: The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities. Conclusions: The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications. Clinical Trials Registration: NCT02771249.

Self-monitoring of blood pressure in hypertension: A systematic review and individual patient data meta-analysis.

BACKGROUND: Self-monitoring of blood pressure (BP) appears to reduce BP in hypertension but important questions remain regarding effective implementation and which groups may benefit most. This individual patient data (IPD) meta-analysis was performed to better understand the effectiveness of BP self-monitoring to lower BP and control hypertension. METHODS AND FINDINGS: Medline, Embase, and the Cochrane Library were searched for randomised trials comparing self-monitoring to no self-monitoring in hypertensive patients (June 2016). Two reviewers independently assessed articles for eligibility and the authors of eligible trials were approached requesting IPD. Of 2,846 articles in the initial search, 36 were eligible. IPD were provided from 25 trials, including 1 unpublished study. Data for the primary outcomes-change in mean clinic or ambulatory BP and proportion controlled below target at 12 months-were available from 15/19 possible studies (7,138/8,292 [86%] of randomised participants). Overall, self-monitoring was associated with reduced clinic systolic blood pressure (sBP) compared to usual care at 12 months (-3.2 mmHg, [95% CI -4.9, -1.6 mmHg]). However, this effect was strongly influenced by the intensity of co-intervention ranging from no effect with self-monitoring alone (-1.0 mmHg [-3.3, 1.2]), to a 6.1 mmHg (-9.0, -3.2) reduction when monitoring was combined with intensive support. Self-monitoring was most effective in those with fewer antihypertensive medications and higher baseline sBP up to 170 mmHg. No differences in efficacy were seen by sex or by most comorbidities. Ambulatory BP data at 12 months were available from 4 trials (1,478 patients), which assessed self-monitoring with little or no co-intervention. There was no association between self-monitoring and either lower clinic or ambulatory sBP in this group (clinic -0.2 mmHg [-2.2, 1.8]; ambulatory 1.1 mmHg [-0.3, 2.5]). Results for diastolic blood pressure (dBP) were similar. The main limitation of this work was that significant heterogeneity remained. This was at least in part due to different inclusion criteria, self-monitoring regimes, and target BPs in included studies. CONCLUSIONS: Self-monitoring alone is not associated with lower BP or better control, but in conjunction with co-interventions (including systematic medication titration by doctors, pharmacists, or patients; education; or lifestyle counselling) leads to clinically significant BP reduction which persists for at least 12 months. The implementation of self-monitoring in hypertension should be accompanied by such co-interventions.

Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control.

Virus-specific CD8+ T cells probably mediate control over HIV replication in rare individuals, termed long-term nonprogressors (LTNPs) or elite controllers. Despite extensive investigation, the mechanisms responsible for this control remain incompletely understood. We observed that HIV-specific CD8+ T cells of LTNPs persisted at higher frequencies than those of treated progressors with equally low amounts of HIV. Measured on a per-cell basis, HIV-specific CD8+ T cells of LTNPs efficiently eliminated primary autologous HIV-infected CD4+ T cells. This function required lytic granule loading of effectors and delivery of granzyme B to target cells. Defective cytotoxicity of progressor effectors could be restored after treatment with phorbol ester and calcium ionophore. These results establish an effector function and mechanism that clearly segregate with immunologic control of HIV. They also demonstrate that lytic granule contents of memory cells are a critical determinant of cytotoxicity that must be induced for maximal per-cell killing capacity.

Adverse effects of antiretroviral therapy on liver hepatocytes and endothelium in HIV patients: An ultrastructural perspective.

Human immunodeficiency virus and antiretroviral therapy (ART) together can be far more detrimental to liver cells than either of the two unaided. However, ultrastructural aspects of the synergistic effects of HIV and ART have been understudied. In a patient cohort receiving ART, this study characterizes ultrastructurally sinusoidal degeneration, hepatocytic aberrations, mitochondrial dysfunction, accumulation of bulky lipid droplets (steatosis), and occlusion of sinusoidal lumina. Mitochondrial dysfunction causes the accumulation of acetyl-CoA which leads to insulin upregulation and resistance, lipid synthesis, and steatosis. Lipid droplets deposited in the sinusoids could be the source of the blood's lipid profile alterations in HIV patients on ART.

Successful Retreatment of Chronic HCV Genotype-1 Infection With Ledipasvir and Sofosbuvir After Initial Short Course Therapy With Direct-Acting Antiviral Regimens.

BACKGROUND: The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy. METHODS: In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR]12). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology. RESULTS: Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 × 10(6) IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The SVR12 rate was 91% (31/34; intention to treat, ITT) after retreatment. One patient relapsed. CONCLUSIONS: In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants. CLINICAL TRIALS REGISTRATION: NCT01805882.

Moderate Sustained Virologic Response Rates With 6-Week Combination Directly Acting Anti-Hepatitis C Virus Therapy in Patients With Advanced Liver Disease.

BACKGROUND: Treatment of genotype 1 hepatitis C virus (HCV) infection with combination directly acting antivirals (DAA) for 8-24 weeks is associated with high rates of sustained virologic response (SVR). We previously demonstrated that adding a third DAA to ledipasvir and sofosbuvir (LDV/SOF) can result in high SVR rates in patients without cirrhosis. In this study, we investigated whether a similar regimen would yield equivalent rates of cure in patients with advanced liver fibrosis. METHODS: Fifty patients were enrolled at the Clinical Research Center of the National Institutes of Health and associated healthcare centers. Enrollment and follow-up data from April 2014 to June 2015 are reported here. Eligible participants were aged ≥18 years, had chronic HCV genotype 1 infection (serum HCV RNA ≥2000 IU/mL), and stage 3-4 liver fibrosis. HCV RNA was measured using a reverse-transcription polymerase chain reaction assay. RESULTS: Of patients treated with LDV, SOF, and the NS3/4A protease inhibitor GS-9451 for 6 weeks, 76% (38 of 50; 95% confidence interval, 60%-85%) had SVR achieved 12 weeks after the end of treatment. There was no statistically significant difference in treatment efficacy between treatment-naive patients (72%, 18 of 25) and those with treatment experience (80%; 20 of 25) (P = .51). Overall, 11 patients (22%) experienced virologic relapse, and 1 (2%) was lost to follow-up at 4 weeks after treatment. No serious adverse events, discontinuations, or deaths were associated with this regimen. CONCLUSIONS: Adding a third DAA to LDV/SOF may result in a moderate SVR rate, lower than that observed in patients without cirrhosis. Significant liver fibrosis remains an impediment to achieving SVR with short-duration DAA therapy. CHINESE CLINICAL TRIALS REGISTRATION: CT01805882.

Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial.

BACKGROUND: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed. AIM: The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease. METHODS: Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis. RESULTS: Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF-ß3 and IL-10 pathways with treatment. CONCLUSION: In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-ß3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials.

The prevalence of metabolic syndrome among law enforcement officers who responded to the 9/11 World Trade Center attacks.

BACKGROUND: Law enforcement officers (LEOs) experience high rates of cardiovascular events compared with the general US population. Metabolic syndrome (MetS) confers an increased risk of cardiovascular disease and all-cause mortality. Data regarding MetS among LEOs are limited. METHODS: We sought to determine the prevalence of MetS and its associated risk factors as well as gender differences among LEOs who participated in the World Trade Center (WTC) Law Enforcement Cardiovascular Screening (LECS) Program from 2008 to 2010. We evaluated a total of 2,497 participants, 40 years and older, who responded to the 9/11 WTC attacks. RESULTS: The prevalence of MetS was 27%, with abdominal obesity and hypertension being the most frequently occurring risk factors. MetS and its risk factors were significantly higher among male compared to female LEOs, except for reduced HDL-cholesterol levels. CONCLUSIONS: MetS is a rising epidemic in the United States, and importantly, approximately one in four LEOs who worked at the WTC site after 9/11 are affected. Am. J. Ind. Med. 59:752-760, 2016. © 2016 Wiley Periodicals, Inc.

Four-Week Direct-Acting Antiviral Regimens in Noncirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: An Open-Label, Nonrandomized Trial.

BACKGROUND: Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) for 6 weeks achieves sustained virologic response (SVR) rates of 95% in some patients. If effective, shorter therapeutic courses could improve adherence and treatment costs. OBJECTIVE: To determine factors predictive of SVR to 4 weeks of DAA treatment in patients with stage F0 to F2 liver fibrosis. DESIGN: Open-label, nonrandomized, phase 2a trial. (Clinical Trials.gov: NCT01805882). SETTING: Single-center. PATIENTS: 50 treatment-naive and predominantly African American patients with HCV genotype 1 infection and early-stage liver fibrosis were sequentially enrolled into 2 treatment groups. INTERVENTION: 25 participants received a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks, and 25 received a 4-drug regimen consisting of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks. MEASUREMENTS: The primary efficacy end point was SVR12 (HCV RNA level below the lower limit of quantification at posttreatment week 12). RESULTS: Forty percent (10 of 25) (95% CI, 21% to 61%) of patients in the 3-drug group and 20% (5 of 25) (CI, 7% to 41%) of those in the 4-drug group achieved SVR12. Exploratory analysis suggested that lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12. Ten patients had baseline HCV variants conferring greater than 20-fold resistance in vitro to at least 1 study DAA; all had viral relapse. Forty-eight percent (12 of 25) of patients receiving the 3-drug regimen and 72% (18 of 25) of those receiving the 4-drug regimen had adverse events, most of which were mild. One participant was lost to follow-up. LIMITATION: Nonrandomized study design and small sample of patients with early-stage fibrosis. CONCLUSION: Combination DAA therapy with 3 or 4 drugs for 4 weeks was well-tolerated but resulted in limited cure rates. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases, National Cancer Institute, and Clinical Center Intramural Program; supported in part by a cooperative research and development agreement between the National Institutes of Health and Gilead Sciences.

Use and Perceived Impact of the County Health Rankings Report in Florida and North Carolina.

OBJECTIVE: Examine overall level of and variation in local health department (LHD) use and perceived impact of the County Health Rankings report (Rankings) in Florida (2010, 2011) and North Carolina (2010-2012, 2013). DESIGN: Two cross-sectional surveys among LHDs. PARTICIPANTS: Local health directors and relevant staff. MAIN OUTCOME MEASURES: Use of the Rankings was measured by asking respondents if their LHD had used the Rankings in any of 10 ways and through assessment of community engagement. Perceived impact was measured by amount of attention the Rankings received from various stakeholders and whether they had already produced or would likely produce any of 7 possible results. RESULTS: Overall, LHDs used the Rankings most often to educate staff in Florida (78%) and North Carolina (56%). Engagement with community groups around the Rankings was variable. Media engagement, through press releases (41%; 40%) or interviews (51%; 36%) in Florida and North Carolina, was moderate. Florida LHDs used the Rankings in more ways and significantly more frequently than North Carolina LHDs. There were few significant differences in perceived impact by state. At least a moderate amount of attention was received from media in Florida (52%) and North Carolina (46%). Twenty-percent of LHDs reported the Rankings received at least moderate attention from the general public in both states and 38% (Florida) and 33% (North Carolina) from policy makers. Tangible benefits to communities from the Rankings, such as having already influenced adoption of new policies, were modest in Florida (3%) and North Carolina (11%). CONCLUSIONS: Results suggest that tangible benefits to communities from use of the Rankings have yet to be fully realized but are encouraging. More effective media engagement could produce the community awareness necessary to maximize the Rankings' potential to mobilize communities for health improvement. State variation in Rankings use suggests that more support to LHDs may be helpful.

Nonalcoholic Steatohepatitis and Hepatic Fibrosis in HIV-1-Monoinfected Adults With Elevated Aminotransferase Levels on Antiretroviral Therapy.

BACKGROUND: Persistent aminotransferase elevations are common in human immunodeficiency virus (HIV)-infected patients on antiretroviral therapy (ART), including those without hepatitis B or C coinfection, but their clinical significance is unknown. METHODS: HIV-infected adults with aminotransferase levels elevated above the upper limit of normal for ≥6 months while receiving ART, and without chronic viral hepatitis or other known causes of chronic liver disease, underwent a detailed metabolic assessment and liver biopsy. RESULTS: Sixty-two HIV-infected subjects completed the study. Forty (65%) had clinically significant liver pathology, including 34 (55%) with nonalcoholic steatohepatitis (NASH) and 11 (18%) with bridging fibrosis, 10 of whom also had NASH. Nonspecific abnormalities alone were seen in 22 (35%) subjects, including mild steatosis, mild to moderate inflammation, and evidence of drug adaptation. Insulin resistance, obesity, and the presence of either of 2 minor alleles in the PNPLA3 gene were significantly associated with increased risk of NASH and fibrosis. NASH and/or fibrosis were not associated with duration of HIV infection or ART, specific antiretroviral drugs, history of opportunistic infection, immune status, or duration of aminotransferase elevation. CONCLUSIONS: HIV-infected adults with chronic aminotransferase elevations while receiving ART have a high rate of liver disease. Noninvasive testing can help identify liver disease in such patients, but liver biopsy is necessary to definitively identify those at risk for liver disease progression and complications. Longitudinal follow-up of this cohort will better characterize the natural history of aminotransferase elevations in this population and identify noninvasive biomarkers of liver disease progression.

Designing for dissemination: lessons in message design from "1-2-3 pap".

Despite a large number of evidence-based health communication interventions tested in private, public, and community health settings, there is a dearth of research on successful secondary dissemination of these interventions to other audiences. This article presents the case study of "1-2-3 Pap," a health communication intervention to improve human papillomavirus (HPV) vaccination uptake and Pap testing outcomes in Eastern Kentucky, and explores strategies used to disseminate this intervention to other populations in Kentucky, North Carolina, and West Virginia. Through this dissemination project, we identified several health communication intervention design considerations that facilitated our successful dissemination to these other audiences; these intervention design considerations include (a) developing strategies for reaching other potential audiences, (b) identifying intervention message adaptations that might be needed, and (c) determining the most appropriate means or channels by which to reach these potential future audiences. Using "1-2-3 Pap" as an illustrative case study, we describe how careful planning and partnership development early in the intervention development process can improve the potential success of enhancing the reach and effectiveness of an intervention to other audiences beyond the audience for whom the intervention messages were originally designed.

Ex vivo sensitivity to broadly neutralizing antibodies and anti-CD4 antibody UB-421 of infectious viral isolates from people living with multidrug-resistant HIV.

BACKGROUND: People living with HIV (PLWH) with multidrug-resistant (MDR) viruses have limited therapeutic options and present challenges regarding clinical management. Recent studies have shown that passive transfer of combination broadly neutralizing antibodies (bNAbs) against HIV and anti-domain 1 CD4 antibody UB-421 can sustain virologic suppression in PLWH in the absence of antiretroviral therapy (ART). Yet studies addressing the therapeutic potential of these antibodies and/or detailed characterization of immunologic and virologic parameters in PLWH with MDR HIV are lacking. METHODS: We examined levels of immune activation and exhaustion markers on CD8+ T cells and the intact HIV proviral DNA burden in 11 PLWH with MDR viruses. For comparison purposes, we included a control group consisting of 27 ART-naïve viremic PLWH. In addition, we determined the sensitivity of infectious viral isolates obtained from the participants against eight bNAbs (3BNC117, 10-1074, VRC01, VRC07, N6, 10E8, PGDM1400, and PGT121) and two anti-CD4 antibodies (ibalizumab and UB-421) using a TZM-bl-based neutralization/suppression assay. FINDINGS: The level of intact HIV proviral DNA was comparable between the two groups (P = 0.29). The levels of activation and exhaustion markers PD-1 (P = 0.0019), TIGIT (P = 0.0222), 2B4 (P = 0.0015), CD160 (P = 0.0015), and CD38+/HLA-DR+ (P = 0.0138) were significantly lower in the MDR group. The infectious viral isolates from each study participant with MDR HIV were resistant to at least 2 bNAbs; however, they were sensitive to at least one of the CD4-binding and non-CD4-binding site antibodies. The majority of participants had ibalizumab-sensitive viruses although the isolates from some participants showed reduced sensitivity to ibalizumab. Notably, none of the 93 viral isolates obtained from the participants were resistant to UB-421. INTERPRETATION: Our data suggest that combination therapy with HIV-specific bNAbs and/or UB-421 in the presence of optimized background therapy could potentially provide sustained virologic suppression in PLWH with MDR HIV. However, this therapeutic strategy needs to be evaluated in human clinical trials. FUNDING: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.