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Type I Interferons (IFN-I) are central to host protection against viral infections 1 . While any cell can produce IFN-I, Plasmacytoid Dendritic Cells (pDCs) make greater quantities and more varieties of these cytokines than any other cell type 2 . However, following an initial burst of IFN- I, pDCs lose their exceptional IFN-I production capacity and become "exhausted", a phenotype that associates with enhanced susceptibility to secondary infections 3-5 . Despite this apparent cost for the host, pDC exhaustion is conserved across multiple species and viral infections, but the underlying mechanisms and the potential evolutionary advantages are not well understood. Here we characterize pDC exhaustion and demonstrate that it is associated with a reduced capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a novel positive regulator of pDC IFN-I production in mice and humans, show that LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following a viral infection, and demonstrate that preservation of LDHB expression is sufficient to partially restore exhausted pDC function in vitro and in vivo . Furthermore, restoring LDHB in vivo in exhausted pDCs increased IFNAR dependent infection- associated pathology. Therefore, our work identifies a novel and conserved mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved but previously unexplained phenomenon of pDC exhaustion.
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During January-August 2021, the Community Prevalence of SARS-CoV-2 Study used time/location sampling to recruit a cross-sectional, population-based cohort to estimate SARS-CoV-2 seroprevalence and nasal swab sample PCR positivity across 15 US communities. Survey-weighted estimates of SARS-CoV-2 infection and vaccine willingness among participants at each site were compared within demographic groups by using linear regression models with inverse variance weighting. Among 22,284 persons >2 months of age and older, median prevalence of infection (prior, active, or both) was 12.9% across sites and similar across age groups. Within each site, average prevalence of infection was 3 percentage points higher for Black than White persons and average vaccine willingness was 10 percentage points lower for Black than White persons and 7 percentage points lower for Black persons than for persons in other racial groups. The higher prevalence of SARS-CoV-2 infection among groups with lower vaccine willingness highlights the disparate effect of COVID-19 and its complications.
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COVID-19 , Vacunas , Adulto , Niño , Humanos , COVID-19/epidemiología , SARS-CoV-2 , Estudios Transversales , Prevalencia , Estudios SeroepidemiológicosRESUMEN
OBJECTIVE: Data on treatment outcomes among minority populations treated with remdesivir are limited. We sought to evaluate outcomes among patients hospitalized with COVID-19 and treated with remdesivir among a predominantly Black and LatinX population. METHODS: This was a retrospective cohort study of adult patients hospitalized with COVID-19 and treated with remdesivir at an urban hospital in Newark, NJ, between May 1, 2020, and April 30, 2021, prior to widespread COVID-19 vaccination uptake. We describe 28-day mortality by demographic, socio-economic, and clinical factors, including clinical status by World Health Organization's (WHO) 8-point Ordinal Scale for Clinical Improvement. RESULTS: A total of 206 patients met study inclusion criteria (52% were male, 41% non-Hispanic Black and 42% Hispanic). Overall mortality at 28 days was 11%. Eighty-one percent of patients with baseline WHO status of 4 or greater recovered by day 14. Mortality was higher among those who were older (p = 0.01), those with underlying diabetes mellitus (p = 0.047), those with more severe illness on admission by WHO Ordinal Scale (WHO status ≥ 4), and those on concomitant tociluzimab or convalescent plasma use. CONCLUSIONS: We found that remdesivir was effective in treating most COVID-19 patients in our study. Traditional risk factors, such as advanced age and underlying co-morbidities, were associated with worse clinical outcomes and deaths.
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BACKGROUND: Hepatic steatosis, including nonalcoholic fatty liver disease (NAFLD), is common among people with HIV (PWH). We present baseline steatosis prevalence and cardiometabolic characteristics among REPRIEVE substudy participants. METHODS: REPRIEVE is an international, primary cardiovascular disease prevention, randomized, controlled trial of pitavastatin calcium vs. placebo among 7769 PWH ages 40-75âyears on antiretroviral therapy (ART) and with low-to-moderate cardiovascular risk. A subset of participants underwent noncontrast computed tomography, with hepatic steatosis defined as mean hepatic attenuation less than 40 HU or liver/spleen ratio less than 1.0, and NAFLD defined as steatosis in the absence of frequent alcohol use or viral hepatitis. RESULTS: Of 687 evaluable persons, median age was 51âyears, BMI 27âkg/m 2 , CD4 + T-cell count 607 cells/µl; 17% natal female sex, 36% Black, 24% Hispanic, and 98% HIV-1 RNA less than 400âcopies/ml. Hepatic steatosis prevalence was 22% (149/687), and NAFLD 21% (96/466). Steatosis/NAFLD prevalence was higher in men and with older age, non-Black race, and higher BMI and waist circumference. Both were associated with BMI greater than 30âkg/m 2 , metabolic syndrome components, higher atherosclerotic cardiovascular disease (ASCVD) risk score, HOMA-IR, LpPLA-2 and hs-CRP, and lower high-density lipoprotein cholesterol. Of HIV-specific/ART-specific characteristics, only history of an AIDS-defining illness was more common among persons with steatosis/NAFLD. After adjusting for age, sex and race/ethnicity, BMI greater than 30âkg/m 2 , HOMA-IR greater than 2.0, Metabolic syndrome and each of its components were associated with NAFLD prevalence. CONCLUSION: In this cohort with controlled HIV and low-to-moderate cardiovascular risk, hepatic steatosis and NAFLD were common and associated with clinically relevant metabolic and inflammatory disturbances but not current HIV-related or ART-related factors.
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Enfermedades Cardiovasculares , Infecciones por VIH , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/complicaciones , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Síndrome Metabólico/complicaciones , Síndrome Metabólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Prevención Primaria , Adulto , AncianoRESUMEN
BACKGROUND: Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous system. METHODS: A5324 was a randomized, double-blind, placebo-controlled, 96-week trial of ART intensification with dolutegravir (DTG) + MVC, DTG + Placebo, or Dual - Placebo in PWH with plasma HIV RNA <50 copies/mL on ART and NCI. The primary outcome was the change on the normalized total z score (ie, the mean of individual NC test z scores) at week 48. RESULTS: Of 357 screened, 191 enrolled: 71% male, 51% Black race, 22% Hispanic ethnicity; mean age 52 years; mean CD4+ T-cells 681 cells/µL. Most (65%) had symptomatic HIV-associated NC disorder. Study drug was discontinued due to an adverse event in 15 (8%) and did not differ between arms (P = .17). Total z score, depressive symptoms, and daily functioning improved over time in all arms with no significant differences between them at week 48 or later. Adjusting for age, sex, race, study site, efavirenz use, or baseline z score did not alter the results. Body mass index modestly increased over 96 weeks (mean increase 0.32 kg/m2, P = .006) and did not differ between arms (P > .10). CONCLUSIONS: This is the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The findings do not support empiric ART intensification as a treatment for NCI in PWH on suppressive ART. They also do not support that DTG adversely affects cognition, mood, or weight.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Masculino , Persona de Mediana Edad , Femenino , Terapia Antirretroviral Altamente Activa/métodos , VIH-1/genética , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos , Carga ViralRESUMEN
CONTEXT: Digital video-based behavioral interventions are effective tools for improving HIV care and treatment outcomes. OBJECTIVE: To assess the costs of the Positive Health Check (PHC) intervention delivered in HIV primary care settings. DESIGN, SETTING, AND INTERVENTION: The PHC study was a randomized trial evaluating the effectiveness of a highly tailored, interactive video-counseling intervention delivered in 4 HIV care clinics in the United States in improving viral suppression and retention in care. Eligible patients were randomized to either the PHC intervention or the control arm. Control arm participants received standard of care (SOC), and intervention arm participants received SOC plus PHC. The intervention was delivered on computer tablets in the clinic waiting rooms. The PHC intervention improved viral suppression among male participants. A microcosting approach was used to assess the program costs, including labor hours, materials and supplies, equipment, and office overhead. PARTICIPANTS: Persons with HIV infection, receiving care in participating clinics. MAIN OUTCOME MEASURES: The primary outcome was the number of patients virally suppressed, defined as having fewer than 200 copies/mL by the end of their 12-month follow-up. RESULTS: A total of 397 (range across sites [range], 95-102) participants were enrolled in the PHC intervention arm, of whom 368 participants (range, 82-98) had viral load data at baseline and were included in the viral load analyses. Of those, 210 (range, 41-63) patients were virally suppressed at the end of their 12-month follow-up visit. The overall annual program cost was $402 274 (range, $65 581-$124 629). We estimated the average program cost per patient at $1013 (range, $649-$1259) and the cost per patient virally suppressed at $1916 (range, $1041-$3040). Recruitment and outreach costs accounted for 30% of PHC program costs. CONCLUSIONS: The costs of this interactive video-counseling intervention are comparable with other retention in care or reengagement interventions.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Masculino , Estados Unidos , Infecciones por VIH/tratamiento farmacológico , Carga Viral , Fármacos Anti-VIH/uso terapéutico , Cumplimiento de la Medicación , Costos y Análisis de CostoRESUMEN
PURPOSE: Black and Latinx MSM and transgender POC disproportionately experience new HIV diagnoses. Determining effective HIV prevention methods requires the inclusion of these communities in research and thorough post-trial experience evaluations. This study sought to evaluate the experiences of Black and Latinx MSM and transgender POC in HIV prevention research and identify facilitators and barriers to continued trials participation. METHODS: A survey was developed in partnership with the community engagement team based on emerging themes during research participant check-ins with the team. The survey was built in REDCap and distributed to participants via text message. The survey assessed experiences with the research process time commitments, study responsibilities, compensation, experiences with Truvada®, characteristics of the research study team and site, barriers to continued study participation, willingness to participate in future studies, and overall satisfaction. All statistical analysis was completed in Stata. RESULTS: Forty-four participants were enrolled in the study. Most participants (98%) were satisfied with their experiences in HIV prevention research. Job or school schedules were the most frequently cited barrier to study participation while Truvada® provision and adequate study visit compensation, length, number, and frequency were facilitators. Participants reported that research staff made them feel comfortable when talking about sexual behaviors, alcohol use, mental health, drug use, housing problems, violence in relationships, and legal problems. CONCLUSIONS: Evaluating the experiences of key communities in HIV prevention research can help identify barriers and facilitators to clinical trials engagement and improve the design of future trials.
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Infecciones por VIH , Minorías Sexuales y de Género , Personas Transgénero , Masculino , Humanos , Personas Transgénero/psicología , Homosexualidad Masculina , Infecciones por VIH/psicología , Combinación Emtricitabina y Fumarato de Tenofovir DisoproxilRESUMEN
BACKGROUND: To determine whether Positive Health Check, a highly tailored video doctor intervention, can improve viral suppression and retention in care. SETTING: Four clinics that deliver HIV primary care. METHODS: A hybrid type 1 effectiveness-implementation randomized trial design was used to test study hypotheses. Participants (N = 799) who were not virally suppressed, were new to care, or had fallen out of care were randomly assigned to receive Positive Health Check or the standard of care alone. The primary endpoint was viral load suppression, and the secondary endpoint was retention in care, both assessed at 12 months, using an intention-to-treat approach. A priori subgroup analyses based on sex assigned at birth and race were examined as well. RESULTS: There were no statistically significant differences between Positive Health Check (N = 397) and standard of care (N = 402) for either endpoint. However, statistically significant group differences were identified from a priori subgroup analyses. Male participants receiving Positive Health Check were more likely to achieve suppression at 12 months than male participants receiving standard of care adjusted risk ratio [aRR] [95% confidence interval (CI)] = 1.14 (1.00 to 1.29), P = 0.046}. For retention in care, there was a statistically significant lower risk for a 6-month visit gap in the Positive Health Check arm for the youngest participants, 18-29 years old [aRR (95% CI) = 0.55 (0.33 to 0.92), P = 0.024] and the oldest participants, 60-81 years old [aRR (95% CI) = 0.49 (0.30 to 0.81), P = 0.006]. CONCLUSIONS: Positive Health Check may help male participants with HIV achieve viral suppression, and younger and older patients consistently attend HIV care. REGISTRY NAME: Positive Health Check Evaluation Trial. Trial ID: 1U18PS004967-01. URL: https://clinicaltrials.gov/ct2/show/NCT03292913.
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Fármacos Anti-VIH , Infecciones por VIH , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Recién Nacido , Masculino , Persona de Mediana Edad , Pruebas Serológicas , Carga Viral , Adulto JovenRESUMEN
BACKGROUND: Deployment of telehealth has been touted as a means of reducing health disparities in underserved groups. However, efforts to reduce regulatory barriers have not been associated with greater telehealth uptake. The goal of this study was to examine engagement with technology among low-income people of color living in Newark, New Jersey. METHODS: Using surveys and focus groups, we examined study participants' daily use of technology (eg, Internet) and comfort with telehealth services (eg, use of teleconferencing for medication refills) before and after COVID-related social distancing mandates went into effect. RESULTS: Use of technology was significantly lower in the pre-COVID period. However, prior months' use of technology had a weak but significant correlation with comfort with telehealth (r = .243, P = .005) in bivariate analyses and was the only significant predictor in multivariate analyses. Analyses of focus group discussions confirmed that lack of experience with technology and distrust of the security and privacy of digital systems were the most important barriers to comfort with telehealth in our sample. CONCLUSION: Our study found that approximately 20% of people in this under-resourced community lacked access to basic technologies necessary for successful deployment of telehealth services. The study's timing provided an unexpected opportunity to compare experiences and attitudes relating to telehealth in 2 regulatory environments. Although uptake of telehealth services increased with the Federal governments' relaxation of regulatory barriers, there was not a similar increase in comfort with telehealth use. Investments in broadband access and equipment should be accompanied by educational programs to increase day-to-day use of and comfort with associated technologies which would improve consumer confidence in telehealth.
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COVID-19 , Telemedicina , Grupos Focales , Humanos , Pobreza , Encuestas y CuestionariosRESUMEN
BACKGROUND: Messenger RNA (mRNA)-1273 vaccine demonstrated 93.2% efficacy against coronavirus disease 2019 (COVID-19) in the Coronavirus Efficacy (COVE) trial. The humoral immunogenicity results are now reported. METHODS: Participants received 2 mRNA-1273 (100â µg) or placebo injections, 28 days apart. Immune responses were evaluated in a prespecified, randomly selected per-protocol immunogenicity population (n = 272 placebo; n = 1185 mRNA-1273). Serum binding antibodies (bAbs) and neutralizing antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-spike protein were assessed at days 1, 29, and 57 by baseline SARS-CoV-2-negative (n = 1197) and SARS-CoV-2-positive (n = 260) status, age, and sex. RESULTS: SARS-CoV-2-negative vaccinees had bAb geometric mean AU/mL levels of 35 753 at day 29 that increased to 316 448 at day 57 and nAb inhibitory dilution 50% titers of 55 at day 29 that rose to 1081 at day 57. In SARS-CoV-2-positive vacinees, the first mRNA-1273 injection elicited bAb and nAb levels that were 11-fold (410 049) and 27-fold (1479) higher than in SARS-CoV-2-negative vaccinees, respectively, and were comparable to levels after 2 injections in uninfected participants. Findings were generally consistent by age and sex. CONCLUSIONS: mRNA-1273 elicited robust serologic immune responses across age, sex, and SARS-CoV-2 status, consistent with its high COVID-19 efficacy. Higher immune responses in those previously infected support a booster-type effect. Clinical Trials Registration. NCT04470427.
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COVID-19 , SARS-CoV-2 , Humanos , Vacuna nCoV-2019 mRNA-1273 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Inmunogenicidad Vacunal , ARN Mensajero , Glicoproteína de la Espiga del CoronavirusRESUMEN
BACKGROUND: Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection. METHODS: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection. RESULTS: The intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified. CONCLUSIONS: CAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.).
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Infecciones por VIH/prevención & control , Inhibidores de Integrasa VIH/administración & dosificación , Profilaxis Pre-Exposición , Piridonas/administración & dosificación , Tenofovir/uso terapéutico , Administración Oral , Adulto , Anciano , Fármacos Anti-VIH/uso terapéutico , Preparaciones de Acción Retardada/administración & dosificación , Método Doble Ciego , Esquema de Medicación , Resistencia a Medicamentos/genética , Femenino , Inhibidores de Integrasa VIH/efectos adversos , Homosexualidad Masculina , Humanos , Inyecciones Intramusculares/efectos adversos , Análisis de Intención de Tratar , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Piridonas/efectos adversos , Personas Transgénero , Adulto JovenRESUMEN
BACKGROUND: We studied risk factors, antibodies, and symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a diverse, ambulatory population. METHODS: A prospective cohort (n = 831) previously undiagnosed with SARS-CoV-2 infection underwent serial testing (SARS-CoV-2 polymerase chain reaction, immunoglobulin G [IgG]) for 6 months. RESULTS: Ninety-three participants (11.2%) tested SARS-CoV-2-positive: 14 (15.1%) asymptomatic, 24 (25.8%) severely symptomatic. Healthcare workers (n = 548) were more likely to become infected (14.2% vs 5.3%; adjusted odds ratio, 2.1; 95% confidence interval, 1.4-3.3) and severely symptomatic (29.5% vs 6.7%). IgG antibodies were detected after 79% of asymptomatic infections, 89% with mild-moderate symptoms, and 96% with severe symptoms. IgG trajectories after asymptomatic infections (slow increases) differed from symptomatic infections (early peaks within 2 months). Most participants (92%) had persistent IgG responses (median 171 days). In multivariable models, IgG titers were positively associated with symptom severity, certain comorbidities, and hospital work. Dyspnea and neurologic changes (including altered smell/taste) lasted ≥ 120 days in ≥ 10% of affected participants. Prolonged symptoms (frequently more severe) corresponded to higher antibody levels. CONCLUSIONS: In a prospective, ethnically diverse cohort, symptom severity correlated with the magnitude and trajectory of IgG production. Symptoms frequently persisted for many months after infection.Clinical Trials Registration. NCT04336215.
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Anticuerpos Antivirales/sangre , COVID-19/diagnóstico , Inmunoglobulina G/sangre , SARS-CoV-2/aislamiento & purificación , Índice de Severidad de la Enfermedad , Adulto , Anticuerpos Antivirales/inmunología , Infecciones Asintomáticas/epidemiología , COVID-19/sangre , COVID-19/epidemiología , COVID-19/transmisión , Comorbilidad , Femenino , Humanos , Inmunoglobulina G/inmunología , Incidencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , SARS-CoV-2/inmunología , Adulto JovenRESUMEN
BACKGROUND: Despite efforts by the AIDS Clinical Trials Group (ACTG) to enroll representative numbers of diverse women, participation in ACTG studies in the United States remains largely white and male. To address this gap in women's participation in ACTG research, a one-year pilot study of dedicated women's outreach workers (WOWs) was proposed. OBJECTIVES: included demonstrating that targeted recruitment efforts can expand community awareness of ACTG research and ensuring successful enrollment of women at the respective clinical research sites. METHODS: The pilot study was conducted at two U.S. sites (Rutgers New Jersey Medical School and Emory Ponce de Leon Center in Atlanta, Georgia). The WOWs worked with site personnel to identify and reach out to women living with HIV and/or Hepatitis B or C at their respective sites and encourage them to join a clinical trial registry for those interested in participating in future clinical trials. RESULTS: The Rutgers WOW approached 127 potential participants (of whom 100 joined the WOW registry) and screened 35 participants for open ACTG studies. The Emory WOW approached 120 participants, enrolling 86 into the WOW registry, and screened 51 potential participants for open ACTG studies during the WOW's tenure. The majority of women screened at both sites were women of color. CONCLUSIONS: The WOW study team identified several lessons learned that can inform future efforts to engage women living with HIV in clinical research. First, success in engaging women is proportional to level of funding and institutional support. Second, there is a need for a more gender-inclusive scientific agenda as women are more likely to participate if studies address topics of interest to them. Third, meaningful engagement is a two-way street.
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Infecciones por VIH , Atención a la Salud , Femenino , Georgia , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , New Jersey , Proyectos Piloto , Estados UnidosRESUMEN
BACKGROUND: We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe coronavirus disease 2019 (COVID-19) using data from a phase 3 remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard of care. METHODS: GS-US-540-5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540-5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, were hospitalized, had oxygen saturation ≤94% on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard of care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality. RESULTS: After the inverse probability of treatment weighting procedure, 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio [aOR] 2.03: 95% confidence interval [CI]: 1.34-3.08, P < .001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (aOR 0.38, 95% CI: .22-.68, P = .001). CONCLUSIONS: In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19. CLINICAL TRIALS REGISTRATION: NCT04292899 and EUPAS34303.
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Tratamiento Farmacológico de COVID-19 , Adenosina Monofosfato/análogos & derivados , Adulto , Alanina/análogos & derivados , Antivirales/uso terapéutico , Estudios de Cohortes , Humanos , Saturación de Oxígeno , Estudios Retrospectivos , SARS-CoV-2 , Nivel de Atención , Resultado del TratamientoRESUMEN
A long-acting injectable formulation of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor, is currently under investigation for use in human immunodeficiency virus (HIV) maintenance therapy. We previously characterized RPV metabolism after oral dosing and identified seven metabolites: four metabolites resulting from mono- or dioxygenation of the 2,6-dimethylphenyl ring itself or either of the two methyl groups located on that ring, one N-linked RPV glucuronide conjugate, and two O-linked RPV glucuronides produced via glucuronidation of mono- and dihydroxymethyl metabolites. However, as is true for most drugs, the metabolism of RPV after injection has yet to be reported. The phase II clinical trial HPTN 076 enrolled 136 HIV-uninfected women and investigated the safety and acceptability of long-acting injectable RPV for use in HIV pre-exposure prophylaxis. Through the analysis of plasma samples from 80 of these participants in the active product arm of the study, we were able to detect 2 metabolites after intramuscular injection of long-acting RPV, 2-hydroxymethyl-RPV, and RPV N-glucuronide. Of the total of 80 individuals, 72 participants exhibited detectable levels of 2-hydroxymethyl-RPV in plasma samples whereas RPV N-glucuronide was detectable in plasma samples of 78 participants. In addition, RPV N-glucuronide was detectable in rectal fluid, cervicovaginal fluid, and vaginal tissue. To investigate potential genetic variation in genes encoding enzymes relevant to RPV metabolism, we isolated genomic DNA and performed next-generation sequencing of CYP3A4, CYP3A5, UGT1A1 and UGT1A4. From these analyses, four missense variants were detected for CYP3A4 whereas one missense variant and one frameshift variant were detected for CYP3A5. A total of eight missense variants of UGT1A4 were detected, whereas two variants were detected for UGT1A1; however, these variants did not appear to account for the observed interindividual variability in metabolite levels. These findings provide insight into the metabolism of long-acting RPV and contribute to an overall understanding of metabolism after oral dosing versus injection. ClinicalTrials.gov Identifier: NCT02165202.
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Fármacos Anti-VIH , Infecciones por VIH , Fármacos Anti-VIH/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Inyecciones Intramusculares , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Rilpivirina/uso terapéuticoRESUMEN
For people with HIV, important transmission prevention strategies include early initiation and adherence to antiretroviral therapy and retention in clinical care with the goal of reducing viral loads as quickly as possible. Consequently, at this point in the HIV epidemic, innovative and effective strategies are urgently needed to engage and retain people in health care to support medication adherence. To address this gap, the Positive Health Check Evaluation Trial uses a type 1 hybrid randomized trial design to test whether the use of a highly tailored video doctor intervention will reduce HIV viral load and retain people with HIV in health care. Eligible and consenting patients from four HIV primary care clinical sites are randomly assigned to receive either the Positive Health Check intervention in addition to the standard of care or the standard of care only. The primary aim is to determine the effectiveness of the intervention. A second aim is to understand the implementation potential of the intervention in clinic workflows, and a third aim is to assess the costs of intervention implementation. The trial findings will have important real-world applicability for understanding how digital interventions that take the form of video doctors can be used to decrease viral load and to support retention in care among diverse patients attending HIV primary care clinics.
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Fármacos Anti-VIH , Infecciones por VIH , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Cumplimiento de la Medicación , Atención Primaria de Salud , Carga ViralRESUMEN
Nucleic acid amplification tests (NAATs) are the primary means of identifying acute infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Accurate and fast test results may permit more efficient use of protective and isolation resources and allow rapid therapeutic interventions. We evaluated the analytical and clinical performance characteristics of the Xpert Xpress SARS-CoV-2 (Xpert) test, a rapid, automated molecular test for SARS-CoV-2. Analytical sensitivity and specificity/interference were assessed with infectious SARS-CoV-2; other infectious coronavirus species, including SARS-CoV; and 85 nasopharyngeal swab specimens positive for other respiratory viruses, including endemic human coronaviruses (hCoVs). Clinical performance was assessed using 483 remnant upper- and lower-respiratory-tract specimens previously analyzed by standard-of-care (SOC) NAATs. The limit of detection of the Xpert test was 0.01 PFU/ml. Other hCoVs, including Middle East respiratory syndrome coronavirus, were not detected by the Xpert test. SARS-CoV, a closely related species in the subgenus Sarbecovirus, was detected by a broad-range target (E) but was distinguished from SARS-CoV-2 (SARS-CoV-2-specific N2 target). Compared to SOC NAATs, the positive agreement of the Xpert test was 219/220 (99.5%), and the negative agreement was 250/261 (95.8%). A third tie-breaker NAAT resolved all but three of the discordant results in favor the Xpert test. The Xpert test provided sensitive and accurate detection of SARS-CoV-2 in a variety of upper- and lower-respiratory-tract specimens. The high sensitivity and short time to results of approximately 45 min may impact patient management.
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Betacoronavirus/aislamiento & purificación , Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Neumonía Viral/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Automatización de Laboratorios/métodos , Betacoronavirus/genética , COVID-19 , Prueba de COVID-19 , Niño , Preescolar , Infecciones por Coronavirus/virología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Nasofaringe/virología , Pandemias , Neumonía Viral/virología , SARS-CoV-2 , Sensibilidad y Especificidad , Adulto JovenRESUMEN
The emergence of the novel coronavirus disease known as COVID-19 creates another health burden for people living with HIV (PLWH) who face multiple morbidities and may be at heightened risk for severe physical health illness from COVID-19. Our abilities to address these morbidities in PLWH must be considered alongside the socially-produced burdens that both place this population at risk for COVID-19 and heighten the likelihood of adverse outcomes. These burdens can affect the physical, emotional, and social well-being of PLWH and interfere with the delivery of effective healthcare and access to HIV treatment. We posit that a syndemic framework can be used to conceptualize the potential impact of COVID-19 among PLWH to inform the development of health programming services.
Asunto(s)
Infecciones por Coronavirus/epidemiología , Coronavirus , Infecciones por VIH/psicología , Accesibilidad a los Servicios de Salud , Neumonía Viral/epidemiología , Determinantes Sociales de la Salud , Betacoronavirus , COVID-19 , Infecciones por Coronavirus/psicología , Atención a la Salud , Abastecimiento de Alimentos , Infecciones por VIH/epidemiología , Servicios de Salud , Humanos , Pandemias , Neumonía Viral/psicología , SARS-CoV-2 , Sindémico , TelemedicinaRESUMEN
Treatment of hepatitis C virus (HCV) infection for patients with human immunodeficiency virus (HIV) has improved with direct acting antivirals. However, outcomes among Black persons treated with ledipasvir/sofosbuvir (LDV/SOF) may be inferior to non-Blacks. We assessed responses to LDV/SOF in a cohort of Black HIV/HCV coinfected persons.Retrospective chart reviews were conducted for Black, genotype 1 (GT1), HIV/HCV coinfected patients treated with LDV/SOF at 3 hospitals in Newark, NJ between January 2014 and July 2016. Data collected included demographics, HCV treatment history, treatment duration, and response.One hundred seventeen HIV/HCV coinfected Black patients started treatment with LDV/SOF but 5 had no follow-up data and 5 prematurely discontinued treatment (1 due to side effects). We included 107âHIV/HCV coinfected patients who completed LDV/SOF at all 3 sites. The study population was 65% male, median age 58 years, 26% had cirrhosis, and 78% had GT1a. Thirty-one percent were treatment experienced but none with prior NS5a treatment. At baseline, median CD4 count was 680âcells/mm, HIV viral load (VL) was <40âcopies/mL in 94% and median HCV VL was 2,257,403âIU/mL. Twenty-nine percent of patients changed antiretroviral treatment before LDV/SOF treatment due to drug interactions. Six, 89, and 12 patients completed 8, 12, and 24 weeks of LDV/SOF, respectively. Overall sustained virologic response rate was 93% with 7 relapses.In this real-world cohort of Black, GT1, HIV/HCV coinfected patients, LDV/SOF had high sustained virologic response 12 weeks post completion of treatment rate of 93%. This data supports the overall high efficacy of LDV/SOF in a historically difficult-to-treat patient population.