ABSTRACT
We compared the serologic responses of 1 dose versus 2 doses of a variant vaccine (Moderna mRNA-1273 Beta/Omicron BA.1 bivalent vaccine) in adults. A 2-dose boosting regimen with a variant vaccine did not increase the magnitude or the durability of the serological responses compared to a single variant vaccine boost.
Subject(s)
2019-nCoV Vaccine mRNA-1273 , Adult , Humans , Vaccines, Combined , Clinical Protocols , RNA, Messenger/geneticsABSTRACT
In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wild-type spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines.
Subject(s)
COVID-19 , Humans , COVID-19/prevention & control , SARS-CoV-2/genetics , Antibodies, Neutralizing , Vaccines, Combined , Antibodies, ViralABSTRACT
BACKGROUND: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence. METHODS: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples. RESULTS: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1ß, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here. CONCLUSIONS: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies.
Subject(s)
Elafin , beta-Defensins , Female , Granulocyte Colony-Stimulating Factor , Humans , Immunoglobulins , Immunologic Factors , Interferons , Interleukin 1 Receptor Antagonist Protein , Interleukin-16 , Interleukin-1alpha , Interleukin-6 , Interleukins , Lactoferrin , Menstrual Cycle , Muramidase , ProgesteroneABSTRACT
During 2007-2019, the percentage of HIV Outpatient Study participants reporting anal or vaginal condomless sex in the past 6 months ranged from a low of 17% among heterosexual males to 59% for men who have sex with men (MSM). MSM reported having had condomless sex more frequently than heterosexual males and females and were the only group in which an increase in condomless sex was observed during the study period (from 39 to 59%). Although persons with undetectable HIV viral load have effectively no risk of transmitting HIV sexually (U = U), there is still the potential risk of transmission or acquisition of other sexually transmitted infections (STIs) when engaging in condomless sex. Continuing education about risks of HIV and STI transmission as well as ongoing screening for and treatment of STIs, retention in HIV treatment, and support for sexual health are critical components of care for people living with HIV.
Subject(s)
HIV Infections , Sexual and Gender Minorities , Sexually Transmitted Diseases , Condoms , Female , HIV Infections/diagnosis , HIV Infections/drug therapy , HIV Infections/epidemiology , Homosexuality, Male , Humans , Male , Outpatients , Sexual Behavior , Sexually Transmitted Diseases/diagnosis , Unsafe SexABSTRACT
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 countsâ >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 56â 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 (Pâ =â .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.
Subject(s)
Aging/genetics , DNA Methylation , Epigenesis, Genetic , HIV Infections , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/genetics , HumansABSTRACT
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.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/prevention & control , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/immunology , Antiviral Agents/adverse effects , Antiviral Agents/immunology , Assisted Living Facilities , COVID-19/epidemiology , Double-Blind Method , Drug Approval , Female , Health Personnel , Humans , Immunization, Passive , Incidence , Infusions, Intravenous , Male , Middle Aged , SARS-CoV-2/isolation & purification , Severity of Illness Index , Skilled Nursing Facilities , Young AdultABSTRACT
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.
Subject(s)
Chlamydia Infections , Gonorrhea , HIV Infections , Sexual and Gender Minorities , Chlamydia Infections/diagnosis , Chlamydia Infections/epidemiology , Gonorrhea/diagnosis , Gonorrhea/epidemiology , HIV , HIV Infections/complications , HIV Infections/epidemiology , Homosexuality, Male , Humans , Incidence , Male , Mass Screening , Outpatients , United States/epidemiologyABSTRACT
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 FCGR2C single-nucleotide polymorphism [SNP] sites) (hazard ratio [HR] = 9.79, P = 0.035) but not among participants without the haplotype (HR = 0.86, P = 0.67); the interaction of vaccine and haplotype effect was significant (P = 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 FCGR3B SNPs) (HR = 2.78, P = 0.058) but not among participants without the haplotype (HR = 0.73, P = 0.44); again, the interaction of vaccine and haplotype was significant (P = 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 FCGR2A SNP and two FCGR2B 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.IMPORTANCE 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.
Subject(s)
B-Lymphocytes/virology , HIV Infections/virology , HIV-1/genetics , Polymorphism, Single Nucleotide , Receptors, IgG/genetics , Vaccines, DNA/administration & dosage , Antibodies, Monoclonal/immunology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , Case-Control Studies , Clinical Trials, Phase II as Topic , Genetic Vectors/administration & dosage , HIV Infections/epidemiology , HIV Infections/genetics , HIV Infections/immunology , HIV Seropositivity , HIV-1/immunology , Humans , Incidence , Phagocytosis , United States/epidemiology , Vaccination , env Gene Products, Human Immunodeficiency Virus/immunologyABSTRACT
BACKGROUND: Suicidal ideation (SI) refers to an individual thinking about, considering or planning suicide. Identifying and characterizing persons with HIV (PWH) at greater risk for SI may lead to better suicide prevention strategies and quality of life improvement. METHODS: Using clinical data gathered from medical chart abstraction for HIV Outpatient Study (HOPS) participants from 2000 to 2017, we assessed SI frequency among PWH in care and explored factors associated with the presence of SI diagnoses using linear mixed models analyses. RESULTS: Among 6706 participants, 224 (3.3%) had a charted diagnosis of SI. Among those with SI, median age (interquartile range [IQR]) was 43.4 years [IQR: 38.7-50.3], median (IQR) CD4+ cell count was 439 cells/mm3 (IQR: 237-686), 71.4% were male, 54% were men who have sex with men (MSM), 25.4% heterosexual, and 13.4% persons who inject drugs. In multivariable analysis, persons at increased risk for SI were more likely to be: <50 years old (adjusted rate ratio [aRR] 1.86, 95% confidence interval [95%CI] 1.36-2.53), non-Hispanic/Latino black (aRR 1.75; 95%CI 1.29-2.38), have CD4+ cell count <350 cells/mm3 (aRR 1.32; 95%CI 1.05-1.65), have a viral load ≥50 copies/mL (aRR 1.49; 95%CI 1.12-1.98), have stopped antiretroviral therapy (aRR 1.46; 95%CI 1.10-1.95), have a history of: alcohol dependence (aRR 2.75; 95%CI 1.67-4.52), and drug overdose (aRR 4.09; 95%CI 2.16-7.71). CONCLUSION: Routine mental health assessment and monitoring are needed in HIV clinical practice to better understand factors associated with SI and to inform the development of preventive interventions.
Subject(s)
HIV Infections/complications , Outpatients , Sexual and Gender Minorities/statistics & numerical data , Suicidal Ideation , Adult , Female , Humans , Male , Middle Aged , Prospective Studies , United StatesABSTRACT
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.
Subject(s)
AIDS-Related Opportunistic Infections/diagnosis , Mycobacteriaceae , Mycobacterium Infections/diagnosis , Pneumonia/etiology , AIDS-Related Opportunistic Infections/microbiology , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Azithromycin/administration & dosage , Azithromycin/therapeutic use , Doxycycline/administration & dosage , Doxycycline/therapeutic use , Drug Therapy, Combination , Humans , Male , Middle Aged , Mycobacterium Infections/drug therapy , Mycobacterium Infections/etiology , Mycobacterium Infections/microbiology , Pneumonia/microbiology , United StatesABSTRACT
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.
Subject(s)
Herpes Genitalis/therapy , Herpesvirus 2, Human/immunology , Immunotherapy , Viral Vaccines/therapeutic use , Adjuvants, Immunologic , Adolescent , Adult , Female , Herpes Genitalis/virology , Humans , Male , Middle Aged , Vaccination , Viral Vaccines/administration & dosage , Virus Shedding , Young AdultABSTRACT
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.
Subject(s)
AIDS Vaccines/immunology , CD8-Positive T-Lymphocytes/physiology , HIV Infections/prevention & control , Antibody Formation/immunology , HIV Antibodies/blood , HIV-1/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin G/classification , MaleABSTRACT
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.
Subject(s)
HIV Infections/complications , Outpatients , Syphilis/epidemiology , Adolescent , Adult , Female , HIV Infections/microbiology , Heterosexuality , Homosexuality, Male , Humans , Incidence , Male , Middle Aged , Prospective Studies , Risk Factors , Sexual Behavior , Sexual and Gender Minorities , United States/epidemiology , Young AdultABSTRACT
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.
ABSTRACT
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.
Subject(s)
HIV Infections/complications , Immune Tolerance , Neoplasms/epidemiology , Adult , Age Factors , Aged , CD4 Lymphocyte Count , Cohort Studies , Female , HIV Infections/pathology , Humans , Male , Middle Aged , Young AdultABSTRACT
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.
Subject(s)
Coinfection/diagnosis , HIV Infections/diagnosis , Homosexuality, Male , Mass Screening , Sexually Transmitted Diseases, Bacterial/diagnosis , Adult , Behavioral Risk Factor Surveillance System , CD4 Lymphocyte Count , Cities/epidemiology , Coinfection/epidemiology , Ethnicity , HIV Infections/epidemiology , Humans , Male , Mass Screening/statistics & numerical data , Patient Acceptance of Health Care/statistics & numerical data , Prospective Studies , Sexual Partners , Sexually Transmitted Diseases, Bacterial/epidemiology , United States/epidemiology , Viral LoadABSTRACT
BACKGROUND: A safe and effective vaccine for the prevention of human immunodeficiency virus type 1 (HIV-1) infection is a global priority. We tested the efficacy of a DNA prime-recombinant adenovirus type 5 boost (DNA/rAd5) vaccine regimen in persons at increased risk for HIV-1 infection in the United States. METHODS: At 21 sites, we randomly assigned 2504 men or transgender women who have sex with men to receive the DNA/rAd5 vaccine (1253 participants) or placebo (1251 participants). We assessed HIV-1 acquisition from week 28 through month 24 (termed week 28+ infection), viral-load set point (mean plasma HIV-1 RNA level 10 to 20 weeks after diagnosis), and safety. The 6-plasmid DNA vaccine (expressing clade B Gag, Pol, and Nef and Env proteins from clades A, B, and C) was administered at weeks 0, 4, and 8. The rAd5 vector boost (expressing clade B Gag-Pol fusion protein and Env glycoproteins from clades A, B, and C) was administered at week 24. RESULTS: In April 2013, the data and safety monitoring board recommended halting vaccinations for lack of efficacy. The primary analysis showed that week 28+ infection had been diagnosed in 27 participants in the vaccine group and 21 in the placebo group (vaccine efficacy, -25.0%; 95% confidence interval, -121.2 to 29.3; P=0.44), with mean viral-load set points of 4.46 and 4.47 HIV-1 RNA log10 copies per milliliter, respectively. Analysis of all infections during the study period (41 in the vaccine group and 31 in the placebo group) also showed lack of vaccine efficacy (P=0.28). The vaccine regimen had an acceptable side-effect profile. CONCLUSIONS: The DNA/rAd5 vaccine regimen did not reduce either the rate of HIV-1 acquisition or the viral-load set point in the population studied. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00865566.).
Subject(s)
AIDS Vaccines/immunology , HIV Infections/prevention & control , HIV-1 , Vaccines, DNA/immunology , AIDS Vaccines/adverse effects , Adult , Double-Blind Method , Female , HIV Infections/epidemiology , HIV Infections/immunology , HIV-1/genetics , HIV-1/isolation & purification , Humans , Immunogenetic Phenomena , Incidence , Male , Middle Aged , RNA, Viral/blood , Transgender Persons , Treatment Failure , Vaccines, DNA/adverse effects , Viral Load , Young AdultABSTRACT
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.
Subject(s)
Disease Susceptibility/immunology , Epithelium/immunology , Follicular Phase/immunology , HIV Infections/immunology , Luteal Phase/immunology , Adolescent , Adult , CD4-Positive T-Lymphocytes/immunology , Cell Adhesion Molecules/metabolism , Female , Follicular Phase/metabolism , Gene Expression Profiling , HIV Infections/virology , HIV-1/immunology , Humans , Interleukin-8/immunology , Luteal Phase/metabolism , Middle Aged , Neutrophils/immunology , Tandem Mass Spectrometry , Young AdultABSTRACT
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.
Subject(s)
HIV Infections/epidemiology , Neoplasms/epidemiology , Adult , Age Distribution , Aged , Anus Neoplasms/epidemiology , Cohort Studies , Colorectal Neoplasms/epidemiology , Comorbidity , Female , Humans , Incidence , Liver Neoplasms/epidemiology , Lung Neoplasms/epidemiology , Lymphoma, Non-Hodgkin/epidemiology , Male , Middle Aged , North America/epidemiology , Proportional Hazards Models , Sarcoma, Kaposi/epidemiologyABSTRACT
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.).