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1.
Pac Symp Biocomput ; 29: 594-610, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38160309

RESUMEN

Access to safe and effective antiretroviral therapy (ART) is a cornerstone in the global response to the HIV pandemic. Among people living with HIV, there is considerable interindividual variability in absolute CD4 T-cell recovery following initiation of virally suppressive ART. The contribution of host genetics to this variability is not well understood. We explored the contribution of a polygenic score which was derived from large, publicly available summary statistics for absolute lymphocyte count from individuals in the general population (PGSlymph) due to a lack of publicly available summary statistics for CD4 T-cell count. We explored associations with baseline CD4 T-cell count prior to ART initiation (n=4959) and change from baseline to week 48 on ART (n=3274) among treatment-naïve participants in prospective, randomized ART studies of the AIDS Clinical Trials Group. We separately examined an African-ancestry-derived and a European-ancestry-derived PGSlymph, and evaluated their performance across all participants, and also in the African and European ancestral groups separately. Multivariate models that included PGSlymph, baseline plasma HIV-1 RNA, age, sex, and 15 principal components (PCs) of genetic similarity explained ∼26-27% of variability in baseline CD4 T-cell count, but PGSlymph accounted for <1% of this variability. Models that also included baseline CD4 T-cell count explained ∼7-9% of variability in CD4 T-cell count increase on ART, but PGSlymph accounted for <1% of this variability. In univariate analyses, PGSlymph was not significantly associated with baseline or change in CD4 T-cell count. Among individuals of African ancestry, the African PGSlymph term in the multivariate model was significantly associated with change in CD4 T-cell count while not significant in the univariate model. When applied to lymphocyte count in a general medical biobank population (Penn Medicine BioBank), PGSlymph explained ∼6-10% of variability in multivariate models (including age, sex, and PCs) but only ∼1% in univariate models. In summary, a lymphocyte count PGS derived from the general population was not consistently associated with CD4 T-cell recovery on ART. Nonetheless, adjusting for clinical covariates is quite important when estimating such polygenic effects.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Humanos , Linfocitos T CD4-Positivos , Estudios Prospectivos , Fármacos Anti-VIH/uso terapéutico , Biología Computacional , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Recuento de Linfocito CD4 , Carga Viral
2.
Ann Intern Med ; 174(8): 1151-1158, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34125574

RESUMEN

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.


Asunto(s)
COVID-19/terapia , Pandemias , Guías de Práctica Clínica como Asunto , Comités Consultivos , COVID-19/epidemiología , Niño , Interpretación Estadística de Datos , Aprobación de Drogas , Medicina Basada en la Evidencia , Femenino , Humanos , Relaciones Interprofesionales , National Institutes of Health (U.S.) , Embarazo , SARS-CoV-2 , Participación de los Interesados , Estados Unidos , Tratamiento Farmacológico de COVID-19
3.
PLoS Genet ; 17(4): e1009464, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33901188

RESUMEN

As a type of relatively new methodology, the transcriptome-wide association study (TWAS) has gained interest due to capacity for gene-level association testing. However, the development of TWAS has outpaced statistical evaluation of TWAS gene prioritization performance. Current TWAS methods vary in underlying biological assumptions about tissue specificity of transcriptional regulatory mechanisms. In a previous study from our group, this may have affected whether TWAS methods better identified associations in single tissues versus multiple tissues. We therefore designed simulation analyses to examine how the interplay between particular TWAS methods and tissue specificity of gene expression affects power and type I error rates for gene prioritization. We found that cross-tissue identification of expression quantitative trait loci (eQTLs) improved TWAS power. Single-tissue TWAS (i.e., PrediXcan) had robust power to identify genes expressed in single tissues, but, often found significant associations in the wrong tissues as well (therefore had high false positive rates). Cross-tissue TWAS (i.e., UTMOST) had overall equal or greater power and controlled type I error rates for genes expressed in multiple tissues. Based on these simulation results, we applied a tissue specificity-aware TWAS (TSA-TWAS) analytic framework to look for gene-based associations with pre-treatment laboratory values from AIDS Clinical Trial Group (ACTG) studies. We replicated several proof-of-concept transcriptionally regulated gene-trait associations, including UGT1A1 (encoding bilirubin uridine diphosphate glucuronosyltransferase enzyme) and total bilirubin levels (p = 3.59×10-12), and CETP (cholesteryl ester transfer protein) with high-density lipoprotein cholesterol (p = 4.49×10-12). We also identified several novel genes associated with metabolic and virologic traits, as well as pleiotropic genes that linked plasma viral load, absolute basophil count, and/or triglyceride levels. By highlighting the advantages of different TWAS methods, our simulation study promotes a tissue specificity-aware TWAS analytic framework that revealed novel aspects of HIV-related traits.


Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo/genética , Transcriptoma/genética , Simulación por Computador , Regulación de la Expresión Génica/genética , Humanos , Especificidad de Órganos/genética , Polimorfismo de Nucleótido Simple/genética
5.
J Neuroimmunol ; 344: 577246, 2020 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-32371201

RESUMEN

We examined the relationship between CSF immune cells and neurocognition and neuronal damage in HIV+ individuals before and after initiating antiretroviral therapy. Multivariate analysis at baseline indicated that greater CD4+ T cell abundance was associated with better cognition (p = .017), while higher CSF HIV RNA was associated with increased neuronal damage (p = .014). Following 24 weeks of antiretroviral therapy, CD8+ T cells, HLA-DR expressing CD4+ and CD8+ T cells, B cells, NK cells, and non-classical monocyte percentage decreased in CSF. Female gender was negatively associated with cognitive performance over time, as was higher percentage of HLA-DR expressing CD8+ T cells at baseline.


Asunto(s)
Terapia Antirretroviral Altamente Activa/métodos , Cognición/fisiología , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/inmunología , Inmunidad Celular/inmunología , Carga Viral/inmunología , Adulto , Cognición/efectos de los fármacos , Femenino , Estudios de Seguimiento , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunidad Celular/efectos de los fármacos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Carga Viral/efectos de los fármacos
6.
AIDS Behav ; 24(7): 2054-2061, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31900813

RESUMEN

Many people living with HIV (PLWHIV) state that they would be willing to take significant risks to be "cured" of the virus. However, how they interpret the word "cure" in this context is not clear. We used a randomized survey to examine whether PLWHIV had a different willingness to take a hypothetical HIV medication if it causes flu-like symptoms, but provides: (a) cure, (b) remission that was labeled "cure", or (c) remission. PLWHIV (n = 454) were more willing to take a medication that provided a "cure" versus a "remission" if the side effects lasted less than 1 year. PLWHIV were more willing to take a medication that provided a remission that was labeled "cure" versus a "remission" (p = 0.01) if the side effects lasted 2 weeks. Clinicians and researchers should be aware of the impact of the word "cure" and ensure that PLWHIV fully understand the possible outcomes of their treatment options.


Asunto(s)
Toma de Decisiones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Pacientes/psicología , Investigadores/psicología , Quimioterapia/psicología , Femenino , Humanos , Intención , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios
7.
Clin Infect Dis ; 71(7): 1655-1663, 2020 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-31621838

RESUMEN

BACKGROUND: Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with bone loss leading to increased fracture rate among persons with HIV (PWH). We previously showed long-acting antiresorptive zoledronic acid (ZOL) prevented ART-induced bone loss through 48 weeks of therapy and here investigate whether protection persisted. METHODS: We randomized 63 nonosteoporotic, treatment-naive adult PWH initiating ART to ZOL (5 mg) versus placebo in a double-blinded, placebo-controlled, phase IIb trial. Here we analyzed the long-term outcome data (144 weeks). Plasma bone turnover markers and bone mineral density (BMD) were quantified at weeks 0, 12, 24, 48, 96, and 144. Primary outcome was change in bone resorption marker C-terminal telopeptide of collagen (CTx). Repeated-measures analyses using mixed linear models were used to estimate and compare study endpoints. RESULTS: At 96 weeks, mean CTx was 62% lower with ZOL relative to placebo (n = 46; CTx = 0.123 vs 0.324 ng/mL; P < .001); at 144 weeks a 25% difference between arms was not statistically significant. At 48 weeks, lumbar spine BMD with ZOL was 11% higher than placebo (n = 60; P < .001) and remained 9-11% higher at 96 (n = 46) and 144 (n = 41; P < .001) weeks. 144 weeks after ZOL infusion, BMD did not change at the lumbar spine (P = .22) but declined at the hip (P = .04) and femoral neck (P = .02). CONCLUSIONS: A single dose of ZOL administered at ART initiation blunts bone resorption and BMD loss at key fracture-prone anatomical sites in treatment-naive PWH for 3 years. A multicenter randomized phase III clinical trial validating these results in a larger population is needed. CLINICAL TRIALS REGISTRATION: NCT01228318.


Asunto(s)
Conservadores de la Densidad Ósea , Infecciones por VIH , Adulto , Densidad Ósea , Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/uso terapéutico , Método Doble Ciego , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Imidazoles/efectos adversos , Ácido Zoledrónico/uso terapéutico
8.
Clin Infect Dis ; 67(11): 1712-1719, 2018 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-29590326

RESUMEN

Background: Herpes zoster (HZ) risk is increased in human immunodeficiency virus (HIV)-infected persons. Live attenuated zoster vaccine (ZV) reduces HZ incidence and severity in adults; safety and immunogenicity data in HIV-infected adults are limited. Methods: We conducted a randomized, double-blind, placebo-controlled trial in HIV-infected adults virally suppressed on antiretroviral therapy (ART). Participants, stratified by CD4+ count (200-349 or ≥350 cells/µL), were randomized 3:1 to receive ZV or placebo on day 0 and week 6. The primary endpoint was serious adverse event or grade 3/4 signs/symptoms within 6 weeks after each dose. Immunogenicity (varicella zoster virus [VZV]-specific glycoprotein enzyme-linked immunosorbent assay and interferon-γ enzyme-linked immunospot assay responses) was assessed at 6 and 12 weeks postvaccination. Results: Of 395 participants (296 ZV vs 99 placebo), 84% were male, 47% white, 29% black, and 22% Hispanic; median age was 49 years. Safety endpoints occurred in 15 ZV and 2 placebo recipients (5.1% [95% confidence interval {CI}, 2.9%-8.2%] vs 2.1% [95% CI, .3%-7.3%]; P = .26). Injection site reactions occurred in 42% of ZV (95% CI, 36.3%-47.9%) vs 12.4% of placebo recipients (95% CI, 6.6%-20.6%) (P < .001). Week 12 median natural log VZV antibody titer was higher for ZV (6.30 [Q1, Q3, 5.64, 6.96]) vs placebo (5.48 [Q1, Q3, 4.63, 6.44]; P < .001) overall and in the high CD4+ stratum (P = .003). VZV antibody titers were similar after 1 or 2 ZV doses. Polymerase chain reaction-confirmed HZ occurred in 2 participants (1 ZV; 1 placebo); none was vaccine strain related. Conclusions: Two doses of ZV in HIV-infected adults suppressed on ART with CD4+ counts ≥200 cells/µL were safe and immunogenic. Clinical Trials Registration: NCT00851786.


Asunto(s)
Terapia Antirretroviral Altamente Activa , Infecciones por VIH/inmunología , Vacuna contra el Herpes Zóster/inmunología , Inmunogenicidad Vacunal , Respuesta Virológica Sostenida , Adulto , Anticuerpos Antivirales/sangre , Recuento de Linfocito CD4 , Método Doble Ciego , Ensayo de Immunospot Ligado a Enzimas , Femenino , Infecciones por VIH/tratamiento farmacológico , Herpesvirus Humano 3 , Humanos , Masculino , Persona de Mediana Edad
9.
AIDS ; 32(7): 885-894, 2018 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-29424771

RESUMEN

OBJECTIVE: Higher incidence of osteopenia and osteoporosis underlie increased rates of fragility fracture in HIV infection. B cells are a major source of osteoprotegerin (OPG), an inhibitor of the key osteoclastogenic cytokine receptor activator of nuclear factor-κB ligand (RANKL). We previously showed that higher B-cell RANKL/OPG ratio contributes to HIV-induced bone loss. T-cell OPG production in humans, however, remains undefined and the contribution of T-cell OPG and RANKL to HIV-induced bone loss has not been explored. DESIGN: We investigated T-cell OPG and RANKL production in ART-naive HIV-infected and uninfected individuals in relation to indices of bone loss in a cross-sectional study. METHODS: T-cell RANKL and OPG production was determined by intracellular staining and flow cytometry, and plasma levels of bone resorption markers were determined by ELISA. RESULTS: We demonstrate for the first time in-vivo human T-cell OPG production, which was significantly lower in HIV-infected individuals and was coupled with moderately higher T-cell RANKL production, resulting in a significantly higher T-cell RANKL/OPG ratio. T-cell RANKL/OPG ratio correlated significantly with BMD-derived z-scores at the hip, lumbar spine and femur neck in HIV-infected individuals with CD4 T-cell counts at least 200 cells/µl but not in those with lower counts. CONCLUSION: Our data suggest that T cells may be a physiologically relevant source of OPG and T-cell RANKL/OPG imbalance is associated with HIV-induced bone loss in CD4 T-cell-sufficient patients. Both B and T lymphocytes may thus contribute to HIV-induced bone loss.


Asunto(s)
Enfermedades Óseas Metabólicas/patología , Infecciones por VIH/complicaciones , Osteoprotegerina/análisis , Ligando RANK/análisis , Linfocitos T/química , Adulto , Recuento de Linfocito CD4 , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Coloración y Etiquetado
11.
J Neurovirol ; 23(1): 106-112, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27400930

RESUMEN

HIV-associated neurocognitive disorders (HANDs) continue to be common and are associated with increased morbidity and mortality. However, the underlying mechanisms in the combination antiretroviral therapy (cART) era are not fully understood. Interferon alpha (IFNα) is an antiviral cytokine found to be elevated in the cerebrospinal fluid (CSF) of individuals with advanced HIV-associated dementia in the pre-cART era. In this cross-sectional study, we investigated the association between IFNα and neurocognitive performance in ambulatory HIV-infected individuals with milder impairment. An eight-test neuropsychological battery representing six cognitive domains was administered. Individual scores were adjusted for demographic characteristics, and a composite neuropsychological score (NPT-8) was calculated. IFNα and CSF neurofilament light chain (NFL) levels were measured using enzyme-linked immunosorbent assay (ELISA). There were 15 chronically infected participants with a history of significant immunocompromise (median nadir CD4+ of 49 cells/µl). Most participants were neurocognitively impaired (mean global deficit score of 0.86). CSF IFNα negatively correlated with three individual tests (Trailmaking A, Trailmaking B, and Stroop Color-Word) as well as the composite NPT-8 score (r = -0.67, p = 0.006). These negative correlations persisted in multivariable analyses adjusting for chronic hepatitis B and C. Additionally, CSF IFNα correlated strongly with CSF NFL, a marker of neuronal damage (rho = 0.748, p = 0.0013). These results extend findings from individuals with severe HIV-associated dementia in the pre-cART era and suggest that IFNα may continue to play a role in HAND pathogenesis during the cART era. Further investigation into the role of IFNα is indicated.


Asunto(s)
Complejo SIDA Demencia/diagnóstico , Complejo SIDA Demencia/inmunología , Antivirales/uso terapéutico , Interferón-alfa/líquido cefalorraquídeo , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Complejo SIDA Demencia/líquido cefalorraquídeo , Complejo SIDA Demencia/tratamiento farmacológico , Adulto , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Cognición/fisiología , Estudios Transversales , Femenino , Expresión Génica , Humanos , Huésped Inmunocomprometido , Interferón-alfa/genética , Interferón-alfa/inmunología , Masculino , Persona de Mediana Edad , Proteínas de Neurofilamentos/genética , Proteínas de Neurofilamentos/inmunología , Pruebas Neuropsicológicas , Pacientes Ambulatorios
12.
J Neurovirol ; 22(6): 816-822, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27245594

RESUMEN

Given the high prevalence of HIV-associated neurocognitive disorders (HAND), we examined the performance of a novel computerized cognitive assessment device (NCAD) for the evaluation of neurocognitive impairment in the setting of HIV. In addition to a standard 8-test neuropsychological battery, each participant underwent testing with the NCAD, which requires approximately 20 min and has been shown to accurately measure neurocognition in elderly individuals. The NCAD yields seven subtest scores in addition to an overall predictive score that is calculated based on subtest results. Thirty-nine HIV-infected participants were included in this study; the majority of which (71.8 %) had undetectable plasma HIV RNA levels and a history of significant immunocompromise (median nadir CD4+ count 34 cells/µl). The mean composite neuropsychological score (NPT-8) was 46.07, and mean global deficit score (GDS) was 0.59. NCAD total subtest accuracy correlated significantly with NPT-8 (Pearson correlation r = 0.59, p < 0.0001) as well as GDS (Spearman's rho = -0.36, p = 0.02). NCAD predictive score also correlated significantly with NPT-8 (Spearman's rho = -0.5601, p = 0.0016) and GDS (Spearman's rho = 0.45, p = 0.0144). When using the most recent nosology of HAND criteria for neurocognitive impairment, the area under the curve (AUC) for NCAD total subtest accuracy was 0.7562 (p = 0.012), while the AUC for the HIV dementia scale was 0.508 (p = 0.930). While not as comprehensive as a full neuropsychological battery, the NCAD shows promise as a rapid screening tool for HIV-infected individuals, and additional research of this device is indicated.


Asunto(s)
Interfaces Cerebro-Computador , Disfunción Cognitiva/diagnóstico , Infecciones por VIH/diagnóstico , Pruebas Neuropsicológicas , Adulto , Área Bajo la Curva , Recuento de Linfocito CD4 , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Diseño de Equipo , Femenino , Georgia , Infecciones por VIH/complicaciones , Infecciones por VIH/fisiopatología , Infecciones por VIH/psicología , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad
13.
Clin Infect Dis ; 63(5): 663-671, 2016 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-27193748

RESUMEN

BACKGROUND: Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with bone loss leading to increased fracture rate among HIV-infected individuals. ART-induced bone loss is most intense within the first 48 weeks of therapy, providing a window for prophylaxis with long-acting antiresorptives. METHODS: In a phase 2, double-blind, placebo-controlled trial, we randomized 63 nonosteoporotic, ART-naive adults with HIV initiating ART with atazanavir/ritonavir + tenofovir/emtricitabine to a single zoledronic acid (ZOL) infusion (5 mg) vs placebo to determine the efficacy of ZOL in mitigating ART-induced bone loss. Plasma bone turnover markers and bone mineral density (BMD) were performed at weeks 0, 12, 24, and 48 weeks. Primary outcome was change in C-terminal telopeptide of collagen at 24 weeks. Repeated-measures analyses using mixed linear models were used to estimate and compare study endpoints. RESULTS: The ZOL arm had a 65% reduction in bone resorption relative to the placebo arm at 24 weeks (0.117 ng/mL vs 0.338 ng/mL; P < .001). This effect of ZOL occurred as early as 12 weeks (73% reduction; P < .001) and persisted through week 48 (57% reduction; P < .001). The ZOL arm had an 8% higher lumbar spine BMD at 12 weeks relative to the placebo arm (P = .003), and remained 11% higher at 24 and 48 weeks. Similar trends were observed in the hip and femoral neck. CONCLUSIONS: A single dose of ZOL administered at ART initiation prevented ART-induced bone loss through the first 48 weeks of ART, the period when ART-induced bone loss is most pronounced. Validation of these results in larger multicenter randomized clinical trials is warranted. CLINICAL TRIALS REGISTRATION: NCT01228318.


Asunto(s)
Antirretrovirales/efectos adversos , Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Imidazoles/uso terapéutico , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control , Adulto , Antirretrovirales/uso terapéutico , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/inducido químicamente , ARN Viral/sangre , Ácido Zoledrónico
14.
AIDS Behav ; 20(12): 2983-2995, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-26979419

RESUMEN

Antiretroviral therapy (ART) can minimize HIV transmission. Prevention benefits may be compromised by barriers to virologic suppression, and by increased condomless sex among those initiating ART. We evaluated condomless sex in a cohort of HIVinfected US individuals poised to initiate ART in a clinical trial. We assessed partner and sex act type, condom use, and perception of infectiousness. Six percent of participants reported as not infectious; men who have sex with men were more likely to perceive high infectivity. Prevalence of condomless sex was 44 %; 74 % of those also reported homosexual acquisition of HIV. Predictors of increased risk of condomless sex included greater numbers of lifetime partners, recent stimulant drug use and an HIV-positive or unknown serostatus partner. In the context of serodifferent partners, lower perception of infectiousness was also associated with a higher risk of condomless sex. Results highlight opportunities for prevention education for HIV infected individuals at ART initiation.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , Seropositividad para VIH/tratamiento farmacológico , Seropositividad para VIH/transmisión , Sexo Inseguro , Adolescente , Adulto , Actitud Frente a la Salud , Estudios de Cohortes , Condones/estadística & datos numéricos , Quimioterapia Combinada , Femenino , Homosexualidad Masculina/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Parejas Sexuales , Encuestas y Cuestionarios , Estados Unidos , Adulto Joven
15.
AIDS ; 30(3): 405-14, 2016 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-26760232

RESUMEN

OBJECTIVE: Antiretroviral therapy (ART) paradoxically intensifies bone loss in the setting of HIV infection. Although the extent of bone loss varies, it occurs with virtually all ART types, suggesting a common pathway that may be aligned with HIV disease reversal. Using an animal model of immunodeficiency we recently demonstrated that immune activation associated with CD4 T-cell reconstitution induces increased production of the osteoclastogenic cytokines RANKL and TNFα by immune cells, driving enhanced bone resorption and loss in bone mineral density. DESIGN: To confirm these findings in humans, we investigated the early kinetics of CD4 T-cell recovery in relation to biomarkers of bone turnover and osteoclastogenic regulators in a prospective 24-week cohort study. METHODS: Clinical data and blood sampling for HIV-RNA PCR, CD4 T-cell counts, bone turnover biomarkers, and osteoclastogenic regulators were obtained from ART-naïve HIV-infected study participants initiating standard doses of lopinavir/ritonavir plus tenofovir disoproxil fumarate/emtricitabine at baseline and at weeks 2, 8, 12, and 24 post ART. RESULTS: C-terminal telopeptide of collagen (CTx) a sensitive biomarker of bone resorption rose by 200% above baseline at week 12, remaining elevated through week 24 (α<0.01), and was associated with significant increases in plasma levels of osteoclastogenic regulators [receptor activator of NF-kB ligand (RANKL), tumor necrosis factor alpha, (TNFα)]. Importantly, the magnitude of CD4 T-cell recovery correlated significantly with CTx (rs = 0.387, α=0.01). CONCLUSION: Our data suggest that ART-induced bone loss occurs early, is aligned with early events of immune reconstitution, and these immune changes provide a unifying mechanism to explain in part the skeletal decline common to all ART.


Asunto(s)
Antirretrovirales/uso terapéutico , Resorción Ósea , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Recuento de Linfocito CD4 , Femenino , Infecciones por VIH/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Ligando RANK/sangre , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangre , Carga Viral , Adulto Joven
16.
Open Forum Infect Dis ; 2(3): ofv085, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26180834

RESUMEN

Background. Some patients are not prescribed atazanavir because of concern about possible jaundice. Atazanavir-associated hyperbilirubinemia correlates with UGT1A1 rs887829 genotype. We examined bilirubin-related discontinuation of atazanavir in participants from AIDS Clinical Trials Group Study A5257. Methods. Discriminatory properties of UGT1A1 T/T genotype for predicting bilirubin-related atazanavir discontinuation through 96 weeks after antiretroviral initiation were estimated. Results. Genetic analyses involved 1450 participants, including 481 who initiated randomized atazanavir/ritonavir. Positive predictive values of rs887829 T/T for bilirubin-related discontinuation of atazanavir (with 95% confidence intervals [CIs]) were 20% (CI, 9%-36%) in Black, 60% (CI, 32%-84%) in White, and 29% (CI, 8%-58%) in Hispanic participants; negative predictive values were 97% (CI, 93%-99%), 95% (CI, 90%-98%), and 97% (CI, 90%-100%), respectively. Conclusions. Bilirubin-related discontinuation of atazanavir was rare in participants not homozygous for rs887829 T/T, regardless of race or ethnicity. We hypothesize that the higher rate of discontinuation among White participants homozygous for rs887829 T/T may reflect differences in physical manifestations of jaundice by race and ethnicity. Selective avoidance of atazanavir initiation among individuals with T/T genotypes would markedly reduce the likelihood of bilirubin-related discontinuation of atazanavir while allowing atazanavir to be prescribed to the majority of individuals. This genetic association will also affect atazanavir/cobicistat.

18.
Clin Infect Dis ; 60(12): 1842-51, 2015 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-25767256

RESUMEN

BACKGROUND: Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24). METHODS: Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression. RESULTS: Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1). CONCLUSIONS: Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation. CLINICAL TRIALS REGISTRATION: NCT 00811954.


Asunto(s)
Fármacos Anti-VIH/farmacología , Sulfato de Atazanavir/farmacología , Darunavir/farmacología , Infecciones por VIH , VIH-1 , Raltegravir Potásico/farmacología , Ritonavir/farmacología , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Sulfato de Atazanavir/administración & dosificación , Sulfato de Atazanavir/uso terapéutico , Glucemia/efectos de los fármacos , Darunavir/administración & dosificación , Darunavir/uso terapéutico , Quimioterapia Combinada , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Humanos , Lípidos/sangre , Masculino , Raltegravir Potásico/administración & dosificación , Raltegravir Potásico/uso terapéutico , Ritonavir/administración & dosificación , Ritonavir/uso terapéutico
19.
PLoS Pathog ; 10(10): e1004497, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25393853

RESUMEN

HIV infection is associated with high rates of osteopenia and osteoporosis, but the mechanisms involved are unclear. We recently reported that bone loss in the HIV transgenic rat model was associated with upregulation of B cell expression of the key osteoclastogenic cytokine receptor-activator of NF-κB ligand (RANKL), compounded by a simultaneous decline in expression of its physiological moderator, osteoprotegerin (OPG). To clinically translate these findings we performed cross-sectional immuno-skeletal profiling of HIV-uninfected and antiretroviral therapy-naïve HIV-infected individuals. Bone resorption and osteopenia were significantly higher in HIV-infected individuals. B cell expression of RANKL was significantly increased, while B cell expression of OPG was significantly diminished, conditions favoring osteoclastic bone resorption. The B cell RANKL/OPG ratio correlated significantly with total hip and femoral neck bone mineral density (BMD), T- and/or Z-scores in HIV infected subjects, but revealed no association at the lumbar spine. B cell subset analyses revealed significant HIV-related increases in RANKL-expressing naïve, resting memory and exhausted tissue-like memory B cells. By contrast, the net B cell OPG decrease in HIV-infected individuals resulted from a significant decline in resting memory B cells, a population containing a high frequency of OPG-expressing cells, concurrent with a significant increase in exhausted tissue-like memory B cells, a population with a lower frequency of OPG-expressing cells. These data validate our pre-clinical findings of an immuno-centric mechanism for accelerated HIV-induced bone loss, aligned with B cell dysfunction.


Asunto(s)
Linfocitos B/metabolismo , Infecciones por VIH/metabolismo , Osteoporosis/metabolismo , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Adulto , Densidad Ósea , Estudios Transversales , Citocinas/metabolismo , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , FN-kappa B/metabolismo , Osteoporosis/etiología , Osteoporosis/patología
20.
Ann Intern Med ; 161(7): 461-71, 2014 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-25285539

RESUMEN

BACKGROUND: Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. OBJECTIVE: To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. DESIGN: A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). SETTING: 57 sites in the United States and Puerto Rico. PATIENTS: Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. INTERVENTION: Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. MEASUREMENTS: Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. RESULTS: Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. LIMITATION: The trial was open-label, and ritonavir was not provided. CONCLUSION: Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1 , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Sulfato de Atazanavir , Darunavir , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Combinación de Medicamentos , Quimioterapia Combinada , Emtricitabina , Femenino , Inhibidores de la Proteasa del VIH/efectos adversos , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Masculino , Oligopéptidos/uso terapéutico , Organofosfonatos/uso terapéutico , Piridinas/uso terapéutico , ARN Viral/aislamiento & purificación , Inhibidores de la Transcriptasa Inversa , Sulfonamidas/uso terapéutico , Tenofovir , Equivalencia Terapéutica , Carga Viral
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