Publications by authors named "Richard M Novak"

71 Publications

Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial.

JAMA 2021 Jun 3. Epub 2021 Jun 3.

Eli Lilly and Co, Indianapolis, Indiana.

Importance: Preventive interventions are needed to protect residents and staff of skilled nursing and assisted living facilities from COVID-19 during outbreaks in their facilities. Bamlanivimab, a neutralizing monoclonal antibody against SARS-CoV-2, may confer rapid protection from SARS-CoV-2 infection and COVID-19.

Objective: To determine the effect of bamlanivimab on the incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities.

Design, Setting, And Participants: Randomized, double-blind, single-dose, phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case. A total of 1175 participants enrolled in the study from August 2 to November 20, 2020. Database lock was triggered on January 13, 2021, when all participants reached study day 57.

Interventions: Participants were randomized to receive a single intravenous infusion of bamlanivimab, 4200 mg (n = 588), or placebo (n = 587).

Main Outcomes And Measures: The primary outcome was incidence of COVID-19, defined as the detection of SARS-CoV-2 by reverse transcriptase-polymerase chain reaction and mild or worse disease severity within 21 days of detection, within 8 weeks of randomization. Key secondary outcomes included incidence of moderate or worse COVID-19 severity and incidence of SARS-CoV-2 infection.

Results: The prevention population comprised a total of 966 participants (666 staff and 300 residents) who were negative at baseline for SARS-CoV-2 infection and serology (mean age, 53.0 [range, 18-104] years; 722 [74.7%] women). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5% vs 15.2%; odds ratio, 0.43 [95% CI, 0.28-0.68]; P < .001; absolute risk difference, -6.6 [95% CI, -10.7 to -2.6] percentage points). Five deaths attributed to COVID-19 were reported by day 57; all occurred in the placebo group. Among 1175 participants who received study product (safety population), the rate of participants with adverse events was 20.1% in the bamlanivimab group and 18.9% in the placebo group. The most common adverse events were urinary tract infection (reported by 12 participants [2%] who received bamlanivimab and 14 [2.4%] who received placebo) and hypertension (reported by 7 participants [1.2%] who received bamlanivimab and 10 [1.7%] who received placebo).

Conclusions And Relevance: Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy.

Trial Registration: ClinicalTrials.gov Identifier: NCT04497987.
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http://dx.doi.org/10.1001/jama.2021.8828DOI Listing
June 2021

INSTI-BASED INITIAL ANTIRETROVIRAL THERAPY IN ADULTS WITH HIV, THE HIV OUTPATIENT STUDY, 2007-2018.

AIDS Res Hum Retroviruses 2021 May 25. Epub 2021 May 25.

CDC, Division of HIV/AIDS Prevention, 1600 Clifton Road, MS E-45, Atlanta, Georgia, United States, 30329;

Background: We evaluated treatment duration and viral suppression (VS) outcomes with integrase strand transfer inhibitor (INSTI)-based regimens versus other contemporary regimens among adults in routine HIV care.

Methods: Eligible participants were seen during January 1, 2007 to June 30, 2018 at nine U.S. HIV clinics, initiated antiretroviral therapy (ART) (baseline date), and had ≥2 clinic visits thereafter. We assessed the probability of remaining on a regimen and achieving HIV RNA < 200 copies/mL on initial INSTI versus non-INSTI ART by Kaplan-Meier analyses and their correlates by Cox regression.

Results: Among 1005 patients, 335 (33.3%) were prescribed an INSTI-containing regimen and 670 (66.7%) a non-INSTI regimen, which may have included non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and other agents. In both groups, most patients were male, non-white, and aged <50 years. Comparing the INSTI with non-INSTI group, the median baseline log10 HIV viral load (copies/mL) was 4.6 vs. 4.5 and the median CD4+ cell count (cells/mm3) was 352 vs. 314. In Kaplan-Meier analysis, the estimated probabilities of remaining on initial regimens at 2 and 4 years were 58% and 40% for INSTI and 51% and 33% for non-INSTI group, respectively (log-rank test p = 0.003. In multivariable models, treatment with an INSTI (vs. non-INSTI) ART was negatively associated with a regimen switch (Hazard Ratio [HR], 0.67, 95% Confidence Interval [CI] 0.56, 0.81, p < 0.001), and was positively associated with achieving viral suppression (HR 1.52; CI 1.29, 1.79, p < 0.001), both irrespective of baseline viral load levels.

Conclusions: Initial INSTI-based regimens were associated with longer durations and better viral suppression than non-INSTI regimens. Results support INSTI regimens as the initial therapy in U.S. treatment guidelines.
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http://dx.doi.org/10.1089/AID.2020.0286DOI Listing
May 2021

Hepatitis C Virus Testing Among Men With Human Immunodeficiency Virus Who Have Sex With Men: Temporal Trends and Racial/Ethnic Disparities.

Open Forum Infect Dis 2021 Apr 17;8(4):ofaa645. Epub 2021 Apr 17.

Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: National guidelines recommend that sexually active people with human immunodeficiency virus (PWH) who are men who have sex with men (MSM) be tested for hepatitis C virus (HCV) infection at least annually. Hepatitis C virus testing rates vary by race/ethnicity in the general population, but limited data are available for PWH.

Methods: We analyzed medical records data from MSM in the HIV Outpatient Study at 9 human immunodeficiency virus (HIV) clinics from January 1, 2011 through December 31, 2019. We excluded observation time after documented past or current HCV infection. We evaluated HCV antibody testing in each calendar year among HCV-seronegative MSM, and we assessed testing correlates by generalized estimating equation analyses.

Results: Of 1829 eligible MSM who were PWH, 1174 (64.2%) were non-Hispanic/Latino white (NHW), 402 (22.0%) non-Hispanic black (NHB), 187 (10.2%) Hispanic/Latino, and 66 (3.6%) of other race/ethnicity. Most were ≥40 years old (68.9%), privately insured (64.5%), with CD4 cell count/mm (CD4) ≥350 (77.0%), and with HIV viral load <200 copies/mL (76.9%). During 2011-2019, 1205 (65.9%) had ≥1 HCV antibody test and average annual HCV percentage tested was 30.3% (from 33.8% for NHB to 28.5% for NHW; < .001). Multivariable factors positively associated ( < .05) with HCV testing included more recent HIV diagnosis, public insurance, lower CD4, prior chlamydia, gonorrhea, syphilis, or hepatitis B virus diagnoses, and elevated liver enzyme levels, but not race/ethnicity.

Conclusions: Although we found no disparities by race/ethnicity in HCV testing, low overall HCV testing rates indicate suboptimal uptake of recommended HCV testing among MSM in HIV care.
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http://dx.doi.org/10.1093/ofid/ofaa645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052496PMC
April 2021

Occurrence of Accelerated Epigenetic Aging and Methylation Disruptions in Human Immunodeficiency Virus Infection Before Antiretroviral Therapy.

J Infect Dis 2021 May;223(10):1681-1689

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Whether accelerated aging develops over the course of chronic human immunodeficiency virus (HIV) infection or can be observed before significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) before the initiation of antiretroviral therapy (ART).

Methods: A total of 378 ART-naive PLWH who had CD4 T-cell counts >500/µL and were enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared with 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in PLWH compared with controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock.

Results: There were a total of 56 639 DMPs and 6103 DMRs at a false discovery rate of <0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age than HIV-negative controls (P = .001), with black race, low CD4 and high CD8 T-cell counts, and duration of HIV being risk factors for age acceleration.

Conclusions: PLWH before the initiation of ART and with preserved immune status show evidence of advanced methylation aging.
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http://dx.doi.org/10.1093/infdis/jiaa599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161637PMC
May 2021

Long-term mucosal T cell activation and homing phenotypes in recipients of an Ad5-vectored HIV vaccine.

Vaccine 2020 08 14;38(36):5814-5821. Epub 2020 Jul 14.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Background: Vaccine-induced mucosal immune responses may be critical for protection against HIV infection, but may also result in short or long-term changes that enhance susceptibility to infection in some individuals, such as those with baseline seroreactivity to vaccine vector antigens. We examined cellular immune responses in blood and gut mucosal tissue roughly two years following vaccination with placebo or the Step study vaccine MRKAd5/HIV-1.

Methods: Participants vaccinated with either placebo or MRKAd5/HIV-1 during participation in HVTN 071, and HVTN 502/Merck 023 underwent phlebotomy and colonic mucosal biopsies via flexible sigmoidoscopy at two timepoints roughly six months apart. After isolation of mononuclear cells, we compared cellular phenotypes and intracellular cytokine responses in vaccine and placebo recipients with and without baseline serological reactivity to Ad5.

Results: Surface expression of activation and gut-homing markers were elevated on CD4 + and CD8 + gut mucosal mononuclear cells (GMMC) in comparison with PBMC (p < 0.01), but were not significantly affected by baseline Ad5 serostatus or receipt of MRKAd5/HIV-1. ICS responses to stimulation with vaccine antigens were of low frequency and magnitude. Ad5 vector responses were seen in vaccinees and baseline seropositive individuals. CD4 + responses to vector antigens were more common in GMMC than PBMC (p < 0.01) and CD8 + responses to HIV gag insert antigens were more frequent in Ad5 seropositive than Ad5 seronegative individuals (p = 0.03).

Conclusion: Vaccination with the Ad5 vectored candidate HIV vaccine MRKAd5/HIV-1 does not lead to long-term changes in the activation state of mucosal CD4 + or CD8 + T lymphocytes regardless of baseline Ad5 serostatus. The findings of this study do not reveal a basis for enhanced susceptibility to HIV infection two years post vaccination.
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http://dx.doi.org/10.1016/j.vaccine.2020.06.043DOI Listing
August 2020

The HIV Outpatient Study-25 Years of HIV Patient Care and Epidemiologic Research.

Open Forum Infect Dis 2020 May 11;7(5):ofaa123. Epub 2020 Apr 11.

Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: The clinical epidemiology of treated HIV infection in the United States has dramatically changed in the past 25 years. Few sources of longitudinal data exist for people with HIV (PWH) spanning that period. Cohort data enable investigating new exposure and disease associations and monitoring progress along the HIV care continuum.

Methods: We synthesized key published findings and conducted primary data analyses in the HIV Outpatient Study (HOPS), an open cohort of PWH seen at public and private HIV clinics since 1993. We assessed temporal trends in health outcomes (1993-2017) and mortality (1994-2017) for 10 566 HOPS participants.

Results: The HOPS contributed to characterizing new conditions (eg, lipodystrophy), demonstrated reduced mortality with earlier HIV treatment, uncovered associations between select antiretroviral agents and cardiovascular disease, and documented remarkable shifts in morbidity from AIDS opportunistic infections to chronic noncommunicable diseases. The median CD4 cell count of participants increased from 244 cells/mm to 640 cells/mm from 1993 to 2017. Mortality fell from 121 to 16 per 1000 person-years from 1994 to 2017 ( < .001). In 2010, 83.7% of HOPS participants had a most recent HIV viral load <200 copies/mL, compared with 92.2% in 2017.

Conclusions: Since 1993, the HOPS has been detecting emerging issues and challenges in HIV disease management. HOPS data can also be used for monitoring trends in infectious and chronic diseases, immunologic and viral suppression status, retention in care, and survival, thereby informing progress toward the Ending the HIV Epidemic initiative.
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http://dx.doi.org/10.1093/ofid/ofaa123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235508PMC
May 2020

The HIV Outpatient Study-25 Years of HIV Patient Care and Epidemiologic Research.

Open Forum Infect Dis 2020 May 11;7(5):ofaa123. Epub 2020 Apr 11.

Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: The clinical epidemiology of treated HIV infection in the United States has dramatically changed in the past 25 years. Few sources of longitudinal data exist for people with HIV (PWH) spanning that period. Cohort data enable investigating new exposure and disease associations and monitoring progress along the HIV care continuum.

Methods: We synthesized key published findings and conducted primary data analyses in the HIV Outpatient Study (HOPS), an open cohort of PWH seen at public and private HIV clinics since 1993. We assessed temporal trends in health outcomes (1993-2017) and mortality (1994-2017) for 10 566 HOPS participants.

Results: The HOPS contributed to characterizing new conditions (eg, lipodystrophy), demonstrated reduced mortality with earlier HIV treatment, uncovered associations between select antiretroviral agents and cardiovascular disease, and documented remarkable shifts in morbidity from AIDS opportunistic infections to chronic noncommunicable diseases. The median CD4 cell count of participants increased from 244 cells/mm to 640 cells/mm from 1993 to 2017. Mortality fell from 121 to 16 per 1000 person-years from 1994 to 2017 ( < .001). In 2010, 83.7% of HOPS participants had a most recent HIV viral load <200 copies/mL, compared with 92.2% in 2017.

Conclusions: Since 1993, the HOPS has been detecting emerging issues and challenges in HIV disease management. HOPS data can also be used for monitoring trends in infectious and chronic diseases, immunologic and viral suppression status, retention in care, and survival, thereby informing progress toward the Ending the HIV Epidemic initiative.
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http://dx.doi.org/10.1093/ofid/ofaa123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235508PMC
May 2020

A community-based model of HIV care for men who have sex with men and transgender women in Chicago.

Int J STD AIDS 2020 02 22;31(2):150-157. Epub 2020 Jan 22.

Division of Infectious Diseases and College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

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http://dx.doi.org/10.1177/0956462419886779DOI Listing
February 2020

Chlamydia and Gonorrhea Incidence and Testing Among Patients in the Human Immunodeficiency Virus Outpatient Study (HOPS), 2007-2017.

Clin Infect Dis 2020 11;71(8):1824-1835

Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: Although chlamydia (CT) and gonorrhea (GC) infections are increasing in the United States, there are limited data on their incidence, testing rates, and associated risk factors among persons living with HIV (PLWH), including by anatomic site among men who have sex with men (MSM).

Methods: We analyzed 2007-2017 medical records data from Human Immunodeficiency Virus (HIV) Outpatient Study (HOPS) participants in care at 9 HIV clinics. We calculated CT (and GC) incidence and testing rates and assessed associations with sociodemographic and clinical factors using log-linear regression.

Results: Among 4727 PLWH, 397 had 881 CT infections and 331 had 861 GC infections, with an incidence of 2.95 and 2.88 per 100 person-years, respectively. From 2007 to 2017, incidence and testing rates increased by approximately 3.0- and 1.9-fold for CT and GC, respectively. Multivariable factors associated with incident CT (GC) included younger age, MSM, and prior diagnoses of sexually transmitted diseases (STDs). Among 1159 MSM, 583 (50.3%) had 844 CT and 843 GC tests during 2016-2017, and 26.6% of tests were 3-site (urethra, rectum, and pharynx), yielding the highest rates of CT (GC) detection. Multivariable factors associated with CT (GC) testing included younger age, non-Hispanic/Latino black race, and having prior STDs.

Conclusions: Recent CT and GC incidence and testing increased among PLWH; however, only half of MSM were tested for CT or GC during 2016-2017 and less than a third of tests were 3-site. To promote sexual health and STD prevention among PLWH who are MSM, research regarding the added value of CT and GC testing across 3 anatomic sites is needed.
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http://dx.doi.org/10.1093/cid/ciz1085DOI Listing
November 2020

Simplification of ART in a patient living with multidrug resistant HIV-1: A case report using twice daily cobicistat and darunavir.

Int J STD AIDS 2019 11 20;30(13):1333-1336. Epub 2019 Oct 20.

Section of Infectious Diseases Pharmacotherapy, Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, IL, USA.

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http://dx.doi.org/10.1177/0956462419841130DOI Listing
November 2019

Mycobacterium conceptionense Pneumonitis in Patient with HIV/AIDS.

Emerg Infect Dis 2019 10;25(10):1986-1988

Approximately 21 human cases of infection with Mycobacterium conceptionense have been reported. However, most cases were outside the United States, and optimal treatment remains uncertain. We report a case of M. conceptionense pneumonitis in a patient with HIV/AIDS in the United States. The patient was cured with azithromycin and doxycycline.
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http://dx.doi.org/10.3201/eid2510.190444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759238PMC
October 2019

Fc Gamma Receptor Polymorphisms Modulated the Vaccine Effect on HIV-1 Risk in the HVTN 505 HIV Vaccine Trial.

J Virol 2019 11 15;93(21). Epub 2019 Oct 15.

Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina, USA

HIV Vaccine Trials Network (HVTN) 505 was a phase 2b efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen. Although the trial was stopped early for lack of overall efficacy, later correlates of risk and sieve analyses generated the hypothesis that the DNA/rAd5 vaccine regimen protected some vaccinees from HIV infection yet enhanced HIV infection risk for others. Here, we assessed whether and how host Fc gamma receptor (FcγR) genetic variations influenced the DNA/rAd5 vaccine regimen's effect on HIV infection risk. We found that vaccine receipt significantly increased HIV acquisition compared with placebo receipt among participants carrying the FCGR2C-TATA haplotype (comprising minor alleles of four single-nucleotide polymorphism [SNP] sites) (hazard ratio [HR] = 9.79,  = 0.035) but not among participants without the haplotype (HR = 0.86,  = 0.67); the interaction of vaccine and haplotype effect was significant ( = 0.034). Similarly, vaccine receipt increased HIV acquisition compared with placebo receipt among participants carrying the FCGR3B-AGA haplotype (comprising minor alleles of the 3 SNPs) (HR = 2.78,  = 0.058) but not among participants without the haplotype (HR = 0.73,  = 0.44); again, the interaction of vaccine and haplotype was significant ( = 0.047). The FCGR3B-AGA haplotype also influenced whether a combined Env-specific CD8 T-cell polyfunctionality score and IgG response correlated significantly with HIV risk; an SNP and two SNPs influenced whether anti-gp140 antibody-dependent cellular phagocytosis correlated significantly with HIV risk. These results provide further evidence that Fc gamma receptor genetic variations may modulate HIV vaccine effects and immune function after HIV vaccination. By analyzing data from the HVTN 505 efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) vaccine regimen, we found that host genetics, specifically Fc gamma receptor genetic variations, influenced whether receiving the DNA/rAd5 regimen was beneficial, neutral, or detrimental to an individual with respect to HIV-1 acquisition risk. Moreover, Fc gamma receptor genetic variations influenced immune responses to the DNA/rAd5 vaccine regimen. Thus, Fc gamma receptor genetic variations should be considered in the analysis of future HIV vaccine trials and the development of HIV vaccines.
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http://dx.doi.org/10.1128/JVI.02041-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803257PMC
November 2019

Effects of Different Doses of GEN-003, a Therapeutic Vaccine for Genital Herpes Simplex Virus-2, on Viral Shedding and Lesions: Results of a Randomized Placebo-Controlled Trial.

J Infect Dis 2018 11;218(12):1890-1899

Department of Medicine, University of Washington Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: GEN-003 is a candidate therapeutic vaccine for genital herpes simplex virus type 2 (HSV-2). We compared virologic and clinical impact of varying GEN-003 doses.

Methods: Adults with symptomatic HSV-2 received placebo or GEN-003 (30 or 60 µg antigen with 25, 50, or 75 µg adjuvant). Viral shedding and lesion rates before vaccination were compared with those measured immediately after vaccination, then at weeks 29-33 and 53-57 after last dose.

Results: Compared with baseline shedding rates, the rate ratios for viral shedding immediately after treatment were as follows: 0.82 (95% confidence interval [CI], 0.49-1.36), 30 µg antigen/25 µg adjuvant (30/25) dose; 0.64 (95% CI, 0.45-0.92), 30/50 dose; 0.63 (95% CI, 0.37-1.10), 30/75 dose; 0.56 (95% CI, 0.36-0.88), 60/25 dose; 0.58 (95% CI, 0.38-0.89), 60/50 dose; 0.45 (95% CI, 0.16-0.79), 60/75 dose; and 0.98 (95% CI, 0.76-1.26), placebo. Lesion rate reductions by GEN-003 ranged from 31% to 69%, but lesion rates also decreased among placebo recipients (62%). Reductions in shedding and lesion rate were durable for 12 months for the 60 µg antigen plus 50 or 75 µg adjuvant groups. No serious adverse events occurred with vaccination.

Conclusions: The most efficacious vaccine combinations for GEN-003 were the 60 µg/50 µg and 60 µg/75 µg doses.
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http://dx.doi.org/10.1093/infdis/jiy415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191615PMC
November 2018

Time spent with HIV viral load above 1500 copies/ml among patients in HIV care, 2000-2014.

AIDS 2018 09;32(14):2033-2042

Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention, Atlanta, Georgia.

Objective: Sexual HIV transmission is more likely to occur when plasma HIV RNA level (viral load) exceeds 1500 copies/ml. We assessed the percentage of person-time spent with viral load above 1500 copies/ml (pPT >1500) among adults with HIV in care.

Design: Observational cohort in eight United States HIV clinics.

Methods: Participants had at least one HIV Outpatient Study (HOPS) clinic visit and at least two viral loads during 2000-2014. We assessed pPT above 1500 in time intervals between consecutive viral load pairs, overall and by ART status. Trends in pPT above 1500 and associations between pPT above 1500 and chosen baseline demographics and clinical characteristics were analyzed using generalized estimating equations.

Results: There were 5873 patients contributing 37 794 person-years; 86.0% person-years had prescribed ART, with increasing coverage over time. Over 2000-2014 pPT above 1500 was 24.2%, decreasing from 38.3% in 2000-2002 to 11.3% in 2012-2014. During observation time with ART prescribed, pPT above 1500 was 16.4% overall, decreasing from 29.9% in 2000-2002 to 8.0% in 2012-2014. pPT above 1500 was higher in patients less than 35 vs. at least 50 years old (31.5 vs. 15.6%), women vs. men (30.8 vs. 22.3%), and black vs. white and Latino/Hispanic patients (32.7 vs. 19.9 and 23.7%, respectively). Multivariable correlates of higher pPT above 1500 included no prescribed ART, being younger, non-Hispanic black vs. white, baseline viral load above 1500 copies/ml or lower CD4 count, and baseline public vs. private insurance.

Conclusion: pPT above 1500 declined during 2000-2014. Results support decreasing HIV transmission risk from persons in HIV care over the last decade, and the need to focus interventions on patient groups more consistently viremic.
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http://dx.doi.org/10.1097/QAD.0000000000001921DOI Listing
September 2018

Risk Factors and Incidence of Syphilis in Human Immunodeficiency Virus (HIV)-Infected Persons: The HIV Outpatient Study, 1999-2015.

Clin Infect Dis 2018 11;67(11):1750-1759

Centers for Disease Control and Prevention, Atlanta, Georgia.

Background: Since 2000, the incidence of syphilis has been increasing, especially among gay, bisexual, and other men who have sex with men (MSM) in the United States. We assessed temporal trends and associated risk factors for newly diagnosed syphilis infections among human immunodeficiency virus (HIV)-infected patients during a 16-year period.

Methods: We analyzed data from the HIV Outpatient Study (HOPS) cohort participants at 10 US HIV clinics during 1999-2015. New syphilis cases were defined based on laboratory parameters and clinical diagnoses. We performed Cox proportional hazards regression analyses of sociodemographic, clinical, and behavioral risk factors for new syphilis infections.

Results: We studied 6888 HIV-infected participants; 641 had 1 or more new syphilis diagnoses during a median follow-up of 5.2 years. Most participants were male (78%), aged 31-50 years, and 57% were MSM. The overall incidence was 1.8 (95% confidence interval [CI], 1.6-1.9) per 100 person-years (PY) and it increased from 0.4 (95% CI, .2-.8) to 2.2 (95% CI, 1.4-3.5) per 100 PY during 1999-2015. In multivariable analyses adjusting for calendar year, risk factors for syphilis included age 18-30 years (hazard ratio [HR], 1.3 [95% CI, 1.1-1.6]) vs 31-40 years, being MSM (HR, 3.1 [95% CI, 2.4-4.1]) vs heterosexual male, and being non-Hispanic black (HR, 1.6 [95% CI, 1.4-1.9]) vs non-Hispanic white.

Conclusions: The increases in the syphilis incidence rate through 2015 reflect ongoing sexual risk and highlight the need for enhanced prevention interventions among HIV-infected patients in care.
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http://dx.doi.org/10.1093/cid/ciy348DOI Listing
November 2018

Modification of the Association Between T-Cell Immune Responses and Human Immunodeficiency Virus Type 1 Infection Risk by Vaccine-Induced Antibody Responses in the HVTN 505 Trial.

J Infect Dis 2018 03;217(8):1280-1288

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, University of Washington, Seattle.

Background: HVTN 505 was a human immunodeficiency virus type 1 (HIV-1) preventive vaccine efficacy trial of a DNA/recombinant adenovirus serotype 5 (rAd5) vaccine regimen. We assessed antibody responses measured 1 month after final vaccination (month 7) as correlates of HIV-1 acquisition risk.

Methods: Binding antibody responses were quantified in serum samples from 25 primary endpoint vaccine cases (diagnosed with HIV-1 infection between month 7 and month 24) and 125 randomly sampled frequency-matched vaccine controls (HIV-1 negative at month 24). We prespecified for a primary analysis tier 6 antibody response biomarkers that measure immunoglobulin G (IgG) and immunoglobulin A (IgA) binding to Env proteins and 2 previously assessed T-cell response biomarkers.

Results: Envelope-specific IgG responses were significantly correlated with decreased HIV-1 risk. Moreover, the interaction of IgG responses and Env-specific CD8+ T-cell polyfunctionality score had a highly significant association with HIV-1 risk after adjustment for multiple comparisons.

Conclusions: Vaccinees with higher levels of Env IgG have significantly decreased HIV-1 risk when CD8+ T-cell responses are low. Moreover, vaccinees with high CD8+ T-cell responses generally have low risk, and those with low CD8+ T-cell and low Env antibody responses have high risk. These findings suggest the critical importance of inducing a robust IgG Env response when the CD8+ T-cell response is low.
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http://dx.doi.org/10.1093/infdis/jiy008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018910PMC
March 2018

Disparities in HIV Viral Load Suppression by Race/Ethnicity Among Men Who Have Sex with Men in the HIV Outpatient Study.

AIDS Res Hum Retroviruses 2018 Apr 13;34(4):357-364. Epub 2018 Feb 13.

Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia.

Maximizing the rates of virologic suppression (VS) among gay, bisexual, and other men who have sex with men (MSM) is essential to limiting HIV morbidity and sexual transmission of HIV in the United States. We analyzed data for MSM of non-Hispanic white (white), non-Hispanic black (black), or Hispanic/Latino race/ethnicity in the HIV Outpatient Study (HOPS) at nine U.S. HIV clinics. VS (HIV RNA <50 copies/ml) was measured closest to January 1, 2015. We modeled factors associated with VS among persons prescribed antiretroviral therapy (ART) for ≥6 months and assessed VS for a subset of participants with behavioral interview data. Among 1,303 MSM studied, 24% were black and 11% were Hispanic/Latino. Fewer black than white or Hispanic/Latino MSM had any documented ART use history (92% vs. 99% and 94%, respectively), and fewer had VS (72% vs. 91% and 81%),  < .001. In analyses of MSM prescribed ART, which adjusted for insurance type, duration of ART use, and CD4 cell count, blacks had lower prevalence of VS than whites [adjusted prevalence ratio (PR) 0.87, confidence interval (95% CI) 0.81-0.93] and Hispanics/Latinos did not (PR 0.95, 95% CI 0.88-1.02). Among 331 MSM with interview data, 6% had no VS, but reported anal sex without a condom with an HIV-uninfected or unknown HIV serostatus male partner in the past 6 months. In this study of HIV-infected MSM, blacks had a significantly lower prevalence of VS than white men. Optimizing HIV care and prevention among all MSM will require addressing underlying risk factors and social determinants of health that contribute to racial/ethnic disparities in HIV outcomes.
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http://dx.doi.org/10.1089/AID.2017.0162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528768PMC
April 2018

Sexually Transmitted Disease Testing of Human Immunodeficiency Virus-Infected Men Who Have Sex With Men: Room for Improvement.

Sex Transm Dis 2017 11;44(11):678-684

From the *Cerner Corporation, Kansas City, MO; †Apex Family Medicine, Denver; ‡Colorado School of Mines, Golden, CO; §University of Illinois, Chicago, IL; and ¶Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA.

Background: In the United States, sexually transmitted infection (STI) testing is recommended at least annually for sexually active men who have sex with men (MSM). We evaluated human immunodeficiency virus (HIV) providers' STI testing practices and frequency of positive test results.

Methods: We analyzed data from HIV Outpatient Study (HOPS) participants who, from 2007 to 2014, completed a confidential survey about risk behaviors. Using medical records data, we assessed the frequency of gonorrhea, chlamydia, and syphilis testing and positive results during the year after the survey for MSM who reported sex without a condom in the prior 6 months. We compared testing frequency and positivity for men having 1, 2 to 3, and 4 or more sexual partners. Correlates of STI testing were assessed using general linear model to derive relative risks (RR) with associated 95% confidence intervals (CI).

Results: Among 719 MSM, testing frequency was 74.5%, 74.3%, and 82.9% for gonorrhea, chlamydia, and syphilis, respectively, and was higher in those men who reported more sexual partners (P < 0.001 for all). In multivariable analysis, testing for gonorrhea was significantly more likely among non-Hispanic black versus white men (RR, 1.17; 95% CI, 1.03-1.33), among men seen in private versus public clinics (RR, 1.16; 95% CI, 1.05-1.28), and among men with 2 to 3 and 4 or more sexual partners versus 1 partner (RR, 1.12; 95% CI, 1.02-1.23, and RR, 1.18; 95% CI, 1.08-1.30, respectively). Correlates of chlamydia and syphilis testing were similar. Test positivity was higher among men with more sexual partners: for gonorrhea 0.0%, 3.0%, and 6.7% for men with 1, 2 to 3, and 4 or more partners, respectively (P < 0.001, syphilis 3.7%, 3.8% and 12.5%, P < 0.001).

Conclusions: Among HIV-infected MSM patients in HIV care who reported sex without a condom, subsequent testing was not documented in clinic records during the following year for up to a quarter of patients. Exploring why STI testing did not occur may improve patient care.
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http://dx.doi.org/10.1097/OLQ.0000000000000664DOI Listing
November 2017

Association of CD4+ T-cell Count, HIV-1 RNA Viral Load, and Antiretroviral Therapy With Kaposi Sarcoma Risk Among HIV-infected Persons in the United States and Canada.

J Acquir Immune Defic Syndr 2017 08;75(4):382-390

*Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale School of Medicine, New Haven, CT; †Department of Internal Medicine, Yale School of Medicine, New Haven, CT; ‡Department of Biostatistics, Yale School of Public Health, Yale School of Medicine, New Haven, CT; §Division of Research, Kaiser Permanente, Oakland, CA; ‖Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; ¶Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL; #Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, CA; **Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA; ††Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; ‡‡Department of Oncology, Princess Marina Hospital, Gaborone, Botswana; §§Mid-Atlantic Permanente Research Institute, Kaiser Permanente Mid-Atlantic States, Rockville, MD; ‖‖Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WA; ¶¶Department of Internal Medicine, Universidad Central del Caribe School of Medicine, Bayamon, Puerto Rico; ##Division of Infectious Diseases, University of Illinois College of Medicine, Chicago, IL; ***Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD; †††Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; ‡‡‡Department of Health Policy and Management, Yale School of Public Health, New Haven, CT; §§§Research Service, Veterans Affairs Connecticut Healthcare System, West Haven, CT; and ‖‖‖Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Kaposi sarcoma (KS) remains common among HIV-infected persons. To better understand KS etiology and to help target prevention efforts, we comprehensively examined a variety of CD4 T-cell count and HIV-1 RNA viral load (VL) measures, as well as antiretroviral therapy (ART) use, to determine independent predictors of KS risk.

Setting: North American AIDS Cohort Collaboration on Research and Design.

Methods: We followed HIV-infected persons during 1996-2009 from 18 cohorts. We used time-updated Cox regression to model relationships between KS risk and recent, lagged, trajectory, and cumulative CD4 count or VL measures, as well as ART use. We used Akaike's information criterion and global P values to derive a final model.

Results: In separate models, the relationship between each measure and KS risk was highly significant (P < 0.0001). Our final mutually adjusted model included recent CD4 count [hazard ratio (HR) for <50 vs. ≥500 cells/μL = 12.4; 95% confidence interval (CI): 6.5 to 23.8], recent VL (HR for ≥100,000 vs. ≤500 copies/mL = 3.8; 95% CI: 2.0 to 7.3), and cumulative (time-weighted mean) VL (HR for ≥100,000 vs. ≤500 copies/mL = 2.5; 95% CI: 1.0 to 5.9). Each P-trend was <0.0001. After adjusting for these measures, we did not detect an independent association between ART use and KS risk.

Conclusions: Our results suggested a multifactorial etiology for KS, with early and late phases of development. The cumulative VL effect suggested that controlling HIV replication promptly after HIV diagnosis is important for KS prevention. We observed no evidence for direct anti-KS activity of ART, independent of CD4 count and VL.
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http://dx.doi.org/10.1097/QAI.0000000000001394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490794PMC
August 2017

HIV Infection, Immunosuppression, and Age at Diagnosis of Non-AIDS-Defining Cancers.

Clin Infect Dis 2017 02;64(4):468-475

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Background: It is unclear whether immunosuppression leads to younger ages at cancer diagnosis among people living with human immunodeficiency virus (PLWH). A previous study found that most cancers are not diagnosed at a younger age in people with AIDS, with the exception of anal and lung cancers. This study extends prior work to include all PLWH and examines associations between AIDS, CD4 count, and age at cancer diagnosis.

Methods: We compared the median age at cancer diagnosis between PLWH in the North American AIDS Cohort Collaboration on Research and Design and the general population using data from the Surveillance, Epidemiology and End Results Program. We used statistical weights to adjust for population differences. We also compared median age at cancer diagnosis by AIDS status and CD4 count.

Results: After adjusting for population differences, younger ages at diagnosis (P < .05) were observed for PLWH compared with the general population for lung (difference in medians = 4 years), anal (difference = 4), oral cavity/pharynx (difference = 2), and kidney cancers (difference = 2) and myeloma (difference = 4). Among PLWH, having an AIDS-defining event was associated with a younger age at myeloma diagnosis (difference = 4; P = .01), and CD4 count <200 cells/µL (vs ≥500) was associated with a younger age at lung cancer diagnosis (difference = 4; P = .006).

Conclusions: Among PLWH, most cancers are not diagnosed at younger ages. However, this study strengthens evidence that lung cancer, anal cancer, and myeloma are diagnosed at modestly younger ages, and also shows younger ages at diagnosis of oral cavity/pharynx and kidney cancers, possibly reflecting accelerated cancer progression, etiologic heterogeneity, or risk factor exposure in PLWH.
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http://dx.doi.org/10.1093/cid/ciw764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850313PMC
February 2017

Microbiome Composition and Function Drives Wound-Healing Impairment in the Female Genital Tract.

PLoS Pathog 2016 Sep 22;12(9):e1005889. Epub 2016 Sep 22.

National HIV and Retrovirology Labs, JC Wilt Center for Infectious Diseases, Public Health Agency of Canada, Winnipeg, Canada.

The mechanism(s) by which bacterial communities impact susceptibility to infectious diseases, such as HIV, and maintain female genital tract (FGT) health are poorly understood. Evaluation of FGT bacteria has predominantly been limited to studies of species abundance, but not bacterial function. We therefore sought to examine the relationship of bacterial community composition and function with mucosal epithelial barrier health in the context of bacterial vaginosis (BV) using metaproteomic, metagenomic, and in vitro approaches. We found highly diverse bacterial communities dominated by Gardnerella vaginalis associated with host epithelial barrier disruption and enhanced immune activation, and low diversity communities dominated by Lactobacillus species that associated with lower Nugent scores, reduced pH, and expression of host mucosal proteins important for maintaining epithelial integrity. Importantly, proteomic signatures of disrupted epithelial integrity associated with G. vaginalis-dominated communities in the absence of clinical BV diagnosis. Because traditional clinical assessments did not capture this, it likely represents a larger underrepresented phenomenon in populations with high prevalence of G. vaginalis. We finally demonstrated that soluble products derived from G. vaginalis inhibited wound healing, while those derived from L. iners did not, providing insight into functional mechanisms by which FGT bacterial communities affect epithelial barrier integrity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033340PMC
http://dx.doi.org/10.1371/journal.ppat.1005889DOI Listing
September 2016

A Matter of Perspective: Comparison of the Characteristics of Persons with HIV Infection in the United States from the HIV Outpatient Study, Medical Monitoring Project, and National HIV Surveillance System.

Open AIDS J 2015 7;9:123-33. Epub 2015 Dec 7.

Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA.

Comparative analyses of the characteristics of persons living with HIV infection (PLWH) in the United States (US) captured in surveillance and other observational databases are few. To explore potential joint data use to guide HIV treatment and prevention in the US, we examined three CDC-funded data sources in 2012: the HIV Outpatient Study (HOPS), a multisite longitudinal cohort; the Medical Monitoring Project (MMP), a probability sample of PLWH receiving medical care; and the National HIV Surveillance System (NHSS), a surveillance system of all PLWH. Overall, data from 1,697 HOPS, 4,901 MMP, and 865,102 NHSS PLWH were analyzed. Compared with the MMP population, HOPS participants were more likely to be older, non-Hispanic/Latino white, not using injection drugs, insured, diagnosed with HIV before 2009, prescribed antiretroviral therapy, and to have most recent CD4+ T-lymphocyte cell count ≥500 cells/mm3 and most recent viral load test<2 00 copies/mL. The MMP population was demographically similar to all PLWH in NHSS, except it tended to be slightly older, HIV diagnosed more recently, and to have AIDS. Our comparative results provide an essential first step for combined epidemiologic data analyses to inform HIV care and prevention for PLWH in the US.
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http://dx.doi.org/10.2174/1874613601509010123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714382PMC
January 2016

Cumulative Incidence of Cancer Among Persons With HIV in North America: A Cohort Study.

Ann Intern Med 2015 Oct;163(7):507-18

Background: Cancer is increasingly common among persons with HIV.

Objective: To examine calendar trends in cumulative cancer incidence and hazard rate by HIV status.

Design: Cohort study.

Setting: North American AIDS Cohort Collaboration on Research and Design during 1996 to 2009.

Participants: 86 620 persons with HIV and 196 987 uninfected adults.

Measurements: Cancer type-specific cumulative incidence by age 75 years and calendar trends in cumulative incidence and hazard rates, each by HIV status.

Results: Cumulative incidences of cancer by age 75 years for persons with and without HIV, respectively, were as follows: Kaposi sarcoma, 4.4% and 0.01%; non-Hodgkin lymphoma, 4.5% and 0.7%; lung cancer, 3.4% and 2.8%; anal cancer, 1.5% and 0.05%; colorectal cancer, 1.0% and 1.5%; liver cancer, 1.1% and 0.4%; Hodgkin lymphoma, 0.9% and 0.09%; melanoma, 0.5% and 0.6%; and oral cavity/pharyngeal cancer, 0.8% and 0.8%. Among persons with HIV, calendar trends in cumulative incidence and hazard rate decreased for Kaposi sarcoma and non-Hodgkin lymphoma. For anal, colorectal, and liver cancer, increasing cumulative incidence, but not hazard rate trends, were due to the decreasing mortality rate trend (-9% per year), allowing greater opportunity to be diagnosed. Despite decreasing hazard rate trends for lung cancer, Hodgkin lymphoma, and melanoma, cumulative incidence trends were not seen because of the compensating effect of the declining mortality rate.

Limitation: Secular trends in screening, smoking, and viral co-infections were not evaluated.

Conclusion: Cumulative cancer incidence by age 75 years, approximating lifetime risk in persons with HIV, may have clinical utility in this population. The high cumulative incidences by age 75 years for Kaposi sarcoma, non-Hodgkin lymphoma, and lung cancer support early and sustained antiretroviral therapy and smoking cessation.
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http://dx.doi.org/10.7326/M14-2768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711936PMC
October 2015

In vitro antiretroviral activity and in vivo toxicity of the potential topical microbicide copper phthalocyanine sulfate.

Virol J 2015 Aug 30;12:132. Epub 2015 Aug 30.

Department of Infectious Disease, University of Illinois at Chicago, Chicago, IL, 60612, USA.

Background: Copper has antimicrobial properties and has been studied for its activity against viruses, including HIV. Copper complexed within a phthalocyanine ring, forming copper (II) phthalocyanine sulfate (CuPcS), may have a role in microbicide development when used intravaginally.

Methods: CuPcS toxicity was tested against cervical epithelial cells, TZM-BL cells, peripheral blood mononuclear cells (PBMC), and cervical explant tissues using cell viability assays. In vivo toxicity was assessed following intravaginal administration of CuPcS in female BALB/C mice and measured using a standardized histology grading system on reproductive tract tissues. Efficacy studies for preventing infection with HIV in the presence of various non-toxic concentrations of CuPcS were carried out in TZM-BL, PBMC, and cervical explant cultures using HIV-1BAL and various pseudovirus subtypes. Non-linear regression was applied to the data to determine the EC50/90 and CC50/90.

Results: CuPcS demonstrated inhibition of HIV infection in PBMCs at concentrations that were non-toxic in cervical epithelial cells and PBMCs with EC50 values of approximately 50 μg/mL. Reproductive tract tissue analysis revealed no toxicity at 100 mg/mL. Human cervical explant tissues challenged with HIV in the presence of CuPcS also revealed a dose-response effect at preventing HIV infection at non-toxic concentrations with an EC50 value of 65 μg/mL.

Conclusion: These results suggest that CuPcS may be useful as a topical microbicide in concentrations that can be achieved in the female genital tract.
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http://dx.doi.org/10.1186/s12985-015-0358-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552998PMC
August 2015

Molecular Signatures of Immune Activation and Epithelial Barrier Remodeling Are Enhanced during the Luteal Phase of the Menstrual Cycle: Implications for HIV Susceptibility.

J Virol 2015 Sep 17;89(17):8793-805. Epub 2015 Jun 17.

National Lab for HIV Immunology, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada, Winnipeg, Manitoba, Canada Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada Unit of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Unlabelled: The variable infectivity and transmissibility of HIV/SHIV has been recently associated with the menstrual cycle, with particular susceptibility observed during the luteal phase in nonhuman primate models and ex vivo human explant cultures, but the mechanism is poorly understood. Here, we performed an unbiased, mass spectrometry-based proteomic analysis to better understand the mucosal immunological processes underpinning this observed susceptibility to HIV infection. Cervicovaginal lavage samples (n = 19) were collected, characterized as follicular or luteal phase using days since last menstrual period, and analyzed by tandem mass spectrometry. Biological insights from these data were gained using a spectrum of computational methods, including hierarchical clustering, pathway analysis, gene set enrichment analysis, and partial least-squares discriminant analysis with LASSO feature selection. Of the 384 proteins identified, 43 were differentially abundant between phases (P < 0.05, ≥2-fold change). Cell-cell adhesion proteins and antiproteases were reduced, and leukocyte recruitment (interleukin-8 pathway, P = 1.41E-5) and extravasation proteins (P = 5.62E-4) were elevated during the luteal phase. LASSO/PLSDA identified a minimal profile of 18 proteins that best distinguished the luteal phase. This profile included cytoskeletal elements and proteases known to be involved in cellular movement. Gene set enrichment analysis associated CD4(+) T cell and neutrophil gene set signatures with the luteal phase (P < 0.05). Taken together, our findings indicate a strong association between proteins involved in tissue remodeling and leukocyte infiltration with the luteal phase, which may represent potential hormone-associated mechanisms of increased susceptibility to HIV.

Importance: Recent studies have discovered an enhanced susceptibility to HIV infection during the progesterone-dominant luteal phase of the menstrual cycle. However, the mechanism responsible for this enhanced susceptibility has not yet been determined. Understanding the source of this vulnerability will be important for designing efficacious HIV prevention technologies for women. Furthermore, these findings may also be extrapolated to better understand the impact of exogenous hormone application, such as the use of hormonal contraceptives, on HIV acquisition risk. Hormonal contraceptives are the most widely used contraceptive method in sub-Saharan Africa, the most HIV-burdened area of the world. For this reason, research conducted to better understand how hormones impact host immunity and susceptibility factors important for HIV infection is a global health priority.
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http://dx.doi.org/10.1128/JVI.00756-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524071PMC
September 2015

T. vaginalis Infection Is Associated with Increased IL-8 and TNFr1 Levels but with the Absence of CD38 and HLADR Activation in the Cervix of ESN.

PLoS One 2015 17;10(6):e0130146. Epub 2015 Jun 17.

Section of Infectious Diseases, Department of Medicine, University of Illinois at Chicago School of Medicine, Chicago, Illinois, 60612, United States of America.

Introduction: Trichomonas vaginalis infection is associated with an increased risk of HIV infection in exposed-seronegative women (ESN) despite their unique immune quiescent profile. It is important to understand possible mechanisms, such as recruitment of activated T cells, by which T. vaginalis could facilitate HIV infection in this population.

Methods: We conducted a cross-sectional study exploring the relationships between T. vaginalis infection, inflammatory markers and T cell activation in the cervix of ESN. During scheduled study visits, participants completed a behavioral questionnaire and physical exam, including sexually transmitted infection (STI) screening and collection of endocervical sponge and cytobrush specimens. T cell and monocyte phenotypes were measured in cervical cytobrush specimens using multi-parameter flow cytometry. Cervical sponge specimens were used to measure cytokines (IL-6, IL-8,IL-10, IP-10, RANTES) using Luminex immunoassays and the immune activation marker soluble TNF receptor 1 using ELISA.

Results: Specimens of 65 women were tested. Twenty-one of these women were infected with T. vaginalis. T. vaginalis infection was associated with significantly increased concentrations of IL-8 (1275pg/ml vs. 566pg/ml, p=.02) and sTNFr1 (430 pg/ml vs. 264 pg/ml, p=.005). However, T. vaginalis infection was not associated with increased percent expression of CCR5+ T cells nor increased CD38 and HLADR activation compared to uninfected women. It was also not associated with increased expression of CCR5+ monocytes.

Conclusions: Among ESN T. vaginalis infection is associated with increased levels of genital pro-inflammatory/immune activation markers IL-8 and TNFr1, but was not associated with an increased percentage of activated endocervical T cells along the CD38 and HLADR pathways. Thus, while T.vaginalis infection may result in some reversal of the immune quiescent profile of ESN, enhanced recruitment of activated CD38 and HLADR expressing CD4+ cells into the endocervix may not be part of the mechanism by which Trichomonas infection alters HIV susceptibility in this unique subset of women.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130146PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470998PMC
April 2016

Pharmacokinetics of ceftaroline in normal body weight and obese (classes I, II, and III) healthy adult subjects.

Antimicrob Agents Chemother 2015 Jul 20;59(7):3956-65. Epub 2015 Apr 20.

College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

The pharmacokinetic profile of ceftaroline has not been well characterized in obese adults. The purpose of this study was to evaluate the pharmacokinetics of ceftaroline in 32 healthy adult volunteers aged 18 to 50 years in the normal, overweight, and obese body size ranges. Subjects were evenly assigned to 1 of 4 groups based on their body mass index (BMI) and total body weight (TBW) (ranges, 22.1 to 63.5 kg/m(2) and 50.1 to 179.5 kg, respectively). Subjects in the lower-TBW groups were matched by age, sex, race/ethnicity, and serum creatinine to the upper-BMI groups. Serial plasma and urine samples were collected over 12 h after the start of the infusion, and the concentrations of ceftaroline fosamil (prodrug), ceftaroline, and ceftaroline M-1 (inactive metabolite) were assayed. Noncompartmental and population pharmacokinetic analyses were used to evaluate the data. The mean plasma ceftaroline maximum concentration and area under the curve were ca. 30% lower in subjects with a BMI of ≥40 kg/m(2) compared to those <30 kg/m(2). A five-compartment pharmacokinetic model with zero-order infusion and first-order elimination optimally described the plasma concentration-time profiles of the prodrug and ceftaroline. Estimated creatinine clearance (eCLCR) and TBW best explained ceftaroline clearance and volume of distribution, respectively. Although lower ceftaroline plasma concentrations were observed in obese subjects, Monte Carlo simulations suggest the probability of target attainment is ≥90% when the MIC is ≤1 μg/ml irrespective of TBW or eCLCR. No dosage adjustment for ceftaroline appears to be necessary based on TBW alone in adults with comparable eCLCR. Confirmation of these findings in infected obese patients is necessary to validate these findings in healthy volunteers. (This study has been registered at ClinicalTrials.gov under registration no. NCT01648127.).
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http://dx.doi.org/10.1128/AAC.00498-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468711PMC
July 2015

Disparities in Initiation of Combination Antiretroviral Treatment and in Virologic Suppression Among Patients in the HIV Outpatient Study, 2000-2013.

J Acquir Immune Defic Syndr 2015 Sep;70(1):23-32

*Department of Medicine, Division of Infectious Diseases, University of Illinois at Chicago, Chicago, IL; †Cerner Corporation, Vienna, VA; ‡Northwestern University Feinberg School of Medicine, Chicago, IL; and §Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA.

Objectives: The National HIV/AIDS Strategy emphasizes virologic suppression (VS) to reduce HIV incidence in the United States. We assessed temporal trends of and disparities in time to combination antiretroviral therapy (cART) initiation and HIV VS in a large demographically diverse cohort of HIV-infected patients.

Design: We included antiretroviral-naive HIV Outpatient Study participants from 2000 to 2013 enrolled within 6 months of their HIV diagnosis who attended ≥2 HIV care-related visits.

Methods: We evaluated time from HIV diagnosis to first use of cART, time from HIV diagnosis to VS, and time from first use of cART to VS. Kaplan-Meier time-to-event curves and Cox proportional hazards models were used to assess temporal trends and correlates of initiating cART and achieving HIV VS (<500 copies per milliliter).

Results: Among 1156 HIV Outpatient Study patients [median age, 37 years; 43.2% non-Hispanic/Latino black (NHB), 14.1% Hispanic/Latino], estimated median times from HIV diagnosis to cART initiation and from HIV diagnosis to VS both shortened by >40% during the 13.5-year study period, reaching, respectively, 2.5 and 5.4 months. In multivariable analyses, NHB patients (as compared with non-Hispanic/Latino white) and those who had injected drugs (as compared with those who did not) initiated cART in a less timely fashion. After adjusting for CD4 cell count and viral load at cART initiation, NHB patients and those aged <30 years (compared with ≥40 years) had lower rates of VS.

Conclusions: Despite improvements in HIV treatment over time, patients who were NHB, younger, or used injection drugs had less favorable outcomes.
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http://dx.doi.org/10.1097/QAI.0000000000000652DOI Listing
September 2015

HIV Sexual Risk and Syndemics among Women in Three Urban Areas in the United States: Analysis from HVTN 906.

J Urban Health 2015 Jun;92(3):572-83

Laboratory of Infectious Disease Prevention, New York Blood Center, 310 E.67th Street, New York, NY, 10065, USA,

Limited data are available on the longitudinal occurrence of syndemic factors among women at risk for HIV infection in the USA and how these factors relate to sexual risk over time. HVTN 906 was a longitudinal study enrolling 799 HIV-uninfected women in three cities. Assessments were done at baseline, 6, 12, and 18 months to assess syndemic factors (low education, low income, unemployment, lack of health insurance, housing instability, substance use, heavy alcohol use, partner violence, incarceration) and sexual risk outcomes. For each sexual risk outcome, a GEE model was fit with syndemic factors or syndemic score (defined as sum of binary syndemics, ranging from 0 to 9), visit, study site, age and race/ethnicity as predictors to examine the multivariable association between syndemic factors and outcomes over time. Odds of unprotected sex while drunk or high were significantly higher when women reported lack of health insurance, substance and heavy alcohol use and partner violence. Housing instability, substance and heavy alcohol use, partner violence and recent incarceration were associated with higher odds of having multiple sexual partners. Odds of sex exchange were significantly higher in the presence of unemployment, housing instability, low education, lack of health insurance, substance and heavy alcohol use, partner violence and incarceration. Housing instability, substance and heavy alcohol use, and partner violence were significantly associated with higher odds of unprotected anal sex. Odds of having a recent STI were significantly higher when women reported housing instability and partner violence. There were significantly higher odds of the reporting of any risk outcomes during follow-up with higher syndemic score. This study highlights a group of women experiencing multiple poor social and health outcomes who need to be the focus of comprehensive interventions.
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http://dx.doi.org/10.1007/s11524-015-9944-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456474PMC
June 2015

Factors associated with cancer incidence and with all-cause mortality after cancer diagnosis among human immunodeficiency virus-infected persons during the combination antiretroviral therapy era.

Open Forum Infect Dis 2014 Mar 27;1(1):ofu012. Epub 2014 May 27.

University of Illinois at Chicago , Chicago, Illinois.

Background: Little is known about survival and factors associated with mortality after cancer diagnosis among persons infected with human immunodeficiency virus (HIV).

Methods: Using Poisson regression, we analyzed incidence rates of acquired immune deficiency syndrome (AIDS)-defining cancers (ADC), non-AIDS-defining infection-related cancers (NADCI), and non-AIDS-defining noninfection-related cancers (NADCNI) among HIV Outpatient Study participants seen at least twice from 1996-2010. All-cause mortality within each cancer category and by calendar period (1996-2000, 2001-2005, 2006-2010) were examined using Kaplan-Meier survival methods and log-rank tests. We identified risk factors for all-cause mortality using multivariable Cox proportional hazard models.

Results: Among 8350 patients, 627 were diagnosed with 664 cancers. Over the 3 time periods, the age- and sex-adjusted incidence rates for ADC and NADCNI declined (both P < .001) and for NADCI did not change (P = .13). Five-year survival differed by cancer category (ADC, 54.5%; NADCI, 65.8%; NADCNI, 65.9%; P = .018), as did median CD4 cell count (107, 241, and 420 cells/mm(3); P < .001) and median log10 viral load (4.1, 2.3, and 2.0 copies/mL; P < .001) at cancer diagnosis, respectively. Factors independently associated with increased mortality for ADC were lower nadir CD4 cell count (hazard ratio [HR] = 3.02; 95% confidence interval [CI], 1.39-6.59) and detectable viral load (≥400 copies/mL; HR = 1.72 [95% CI, 1.01-2.94]) and for NADCNI, age (HR = 1.50 [95% CI, 1.16-1.94]), non-Hispanic black race (HR = 1.92 [95% CI, 1.15-3.24]), lower nadir CD4 cell count (HR = 1.77 [95% CI, 1.07-2.94]), detectable viral load (HR = 1.96 [95% CI, 1.18-3.24]), and current or prior tobacco use (HR = 3.18 [95% CI, 1.77-5.74]).

Conclusions: Since 1996, ADC and NADCNI incidence rates have declined. Survival after cancer diagnosis has increased with concomitant increases in CD4 cell count in recent years. Advances in HIV therapy, including early initiation of combination antiretroviral therapy, may help reduce mortality risk among HIV-infected persons with cancer.
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http://dx.doi.org/10.1093/ofid/ofu012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324175PMC
March 2014