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1.
Drug Dev Res ; 82(7): 873-879, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34110032

RESUMEN

COVID-19 manifests as a mild disease in most people but can progress to severe disease in nearly 20% of individuals. Disease progression is likely driven by a cytokine storm, either directly stimulated by SARS-CoV-2 or by increased systemic inflammation in which the gut might play an integral role. SARS-CoV-2 replication in the gut may cause increased intestinal permeability, alterations to the fecal microbiome, and increased inflammatory cytokines. Each effect may lead to increased systemic inflammation and the transport of cytokines and inflammatory antigens from the gut to the lung. Few interventions are being studied to treat people with mild disease and prevent the cytokine storm. Serumderived bovine immunoglobulin/protein isolate (SBI) may prevent progression by (1) binding and neutralizing inflammatory antigens, (2) decreasing gut permeability, (3) interfering with ACE2 binding by viral proteins, and (4) improving the fecal microbiome. SBI is therefore a promising intervention to prevent disease progression in COVID-19 patients.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Inmunización Pasiva/métodos , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , COVID-19/complicaciones , Bovinos , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/prevención & control , Microbioma Gastrointestinal , Tracto Gastrointestinal/patología , Humanos , Permeabilidad
3.
PLoS Pathog ; 12(1): e1005381, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26795282

RESUMEN

Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.


Asunto(s)
Antagonistas de los Receptores CCR5/administración & dosificación , Infecciones por VIH/inmunología , Inhibidores de Integrasa VIH/administración & dosificación , Inmunidad Mucosa/efectos de los fármacos , Subgrupos de Linfocitos T/efectos de los fármacos , Adulto , Alquinos , Fármacos Anti-VIH/administración & dosificación , Benzoxazinas/administración & dosificación , Cromatografía Líquida de Alta Presión , Ciclohexanos/administración & dosificación , Ciclopropanos , Combinación de Medicamentos , Combinación Emtricitabina y Fumarato de Tenofovir Disoproxil/administración & dosificación , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Infecciones por VIH/tratamiento farmacológico , Humanos , Activación de Linfocitos/efectos de los fármacos , Masculino , Maraviroc , Proyectos Piloto , Raltegravir Potásico/administración & dosificación , Subgrupos de Linfocitos T/inmunología , Triazoles/administración & dosificación
4.
J Infect Dis ; 216(9): 1159-1163, 2017 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-29040604

RESUMEN

A nested case-cohort study was performed in participants of a clinical trial of first-line human immunodeficiency virus treatments to investigate plasma biomarkers of inflammation and microbial translocation for their association with immune reconstitution inflammatory syndrome (IRIS). Fifty-one of 1452 participants with baseline CD4 count <350 cells/µL developed IRIS. Plasma from 51 IRIS cases, including 6 stratified by preenrollment CD4 count ≤200 cells/µL, were analyzed and compared to 94 non-IRIS controls. At baseline, CXCL10, lipopolysaccharide, soluble CD14, 16S ribosomal DNA, and interferon-α2 were associated with greater risk of IRIS. Systemic inflammation through persistent monocyte activation and microbial translocation appear to be important in IRIS pathogenesis.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Biomarcadores/sangre , Citocinas/sangre , Infecciones por VIH/tratamiento farmacológico , Síndrome Inflamatorio de Reconstitución Inmune/sangre , Síndrome Inflamatorio de Reconstitución Inmune/inmunología , Translocación Genética/inmunología , Estudios de Cohortes , Humanos
5.
J Infect Dis ; 216(7): 813-818, 2017 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-28968888

RESUMEN

Plasma, duodenal, and rectal tissue antiretroviral therapy (ART) drug concentrations, human immunodeficiency virus (HIV) RNA and HIV DNA copy numbers, and recovery of mucosal immunity were measured before and 9 months after initiation of 3 different ART regimens in 26 subjects. Plasma and tissue HIV RNA correlated at baseline and when 9-month declines were compared, suggesting that these compartments are tightly associated. Antiretroviral tissue:blood penetration ratios were above the 50% inhibitory concentration values in almost 100% of cases. There were no correlations between drug concentrations and HIV DNA/RNA. Importantly, no evidence was found for residual viral replication or deficient tissue drug penetration to account for delayed gastrointestinal-associated lymphoid tissue immune recovery.


Asunto(s)
Benzoxazinas/uso terapéutico , Ciclohexanos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Tejido Linfoide/efectos de los fármacos , Raltegravir Potásico/uso terapéutico , Triazoles/uso terapéutico , Adulto , Alquinos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/administración & dosificación , Ciclohexanos/administración & dosificación , Ciclopropanos , ADN Viral , Duodeno/efectos de los fármacos , Duodeno/metabolismo , Femenino , Humanos , Tejido Linfoide/metabolismo , Masculino , Maraviroc , ARN Viral , Raltegravir Potásico/administración & dosificación , Recto/efectos de los fármacos , Recto/metabolismo , Triazoles/administración & dosificación
6.
J Infect Dis ; 214(1): 65-72, 2016 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-26962236

RESUMEN

BACKGROUND: Both wasting and obesity are associated with inflammation, but the extent to which body weight changes influence inflammation during human immunodeficiency virus infection is unknown. METHODS: Among a random virologically suppressed participants of the Prospective Evaluation of Antiretrovirals in Resource-Limited Settings trial, inflammatory markers were measured at weeks 0, 24, and 48 after antiretroviral therapy (ART) initiation. Associations between both baseline and change in body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) and changes in inflammation markers were assessed using random effects models. RESULTS: Of 246 participants, 27% were overweight/obese (BMI, ≥ 25), and 8% were underweight (BMI < 18.5) at baseline. After 48 weeks, 37% were overweight/obese, and 3% were underweight. While level of many inflammatory markers decreased 48 weeks after ART initiation in the overall group, the decrease in C-reactive protein (CRP) level was smaller in overweight/obese participants (P = .01), and the decreases in both CRP (P = .01) and interleukin 18 (P = .02) levels were smaller in underweight participants. Each 1-unit gain in BMI among overweight/obese participants was associated with a 0.02-log10 increase in soluble CD14 level (P = .05), while each 1-unit BMI gain among underweight participants was associated with a 9.32-mg/L decrease in CRP level (P = .001). CONCLUSIONS: Being either overweight or underweight at ART initiation was associated with heightened systemic inflammation. While weight gain among overweight/obese persons predicted increased inflammation, weight gain among underweight persons predicted reduced inflammation.


Asunto(s)
Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Peso Corporal/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Inflamación/inducido químicamente , Aumento de Peso/efectos de los fármacos , Pérdida de Peso/efectos de los fármacos , Adulto , Brasil , Estudios de Cohortes , Femenino , Haití , Humanos , India , Malaui , Masculino , Perú , Estudios Prospectivos , Sudáfrica , Tailandia , Estados Unidos , Zimbabwe
7.
HIV Clin Trials ; 16(2): 72-80, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25923596

RESUMEN

BACKGROUND: One of the more clinically relevant co-morbidities in HIV-infected patients is the development of progressive liver disease due to hepatitis B virus (HBV) or hepatitis C virus (HCV). In addition, hepatotoxicity has been observed with prolonged use of antiretroviral agents. OBJECTIVE: To evaluate the hepatic safety of maraviroc in combination with other antiretroviral agents in HIV-1-infected subjects co-infected with HCV and/or HBV. METHODS: In this 148-week randomized, double-blind, placebo-controlled, multicentre study (NCT01327547), subjects received maraviroc twice daily (n = 70) or placebo (n = 67) in combination with other antiretroviral agents. PRIMARY ENDPOINT: the percentage at week 48 of subjects with Grade 3 and Grade 4 ALT abnormalities, defined as >5 × upper limit of normal (ULN) if baseline ALT ≤ ULN or >3.5 × baseline if baseline ALT>ULN in the maraviroc versus the placebo arm. RESULTS: At week 48, one subject in each group had met the primary endpoint definition. No subjects met protocol-defined liver stopping criteria and there were no cases of Hy's law or treatment-related hepatobiliary serious adverse events. No significant difference in change from baseline in enhanced liver fibrosis or hepatic elastography was observed between groups. Treatment-related hepatobiliary adverse events were reported in one and two subjects receiving maraviroc and placebo, respectively; discontinuations due to treatment-related AEs occurred in four and two subjects receiving maraviroc and placebo, respectively; two deaths were reported in the placebo group. CONCLUSIONS: The use of maraviroc does not increase hepatotoxicity in HIV-1-infected subjects co-infected with HCV and/or HBV through 48 weeks of treatment.


Asunto(s)
Antirretrovirales/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Hepatitis B/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Adulto , Anciano , Antagonistas de los Receptores CCR5/administración & dosificación , Coinfección , Ciclohexanos/administración & dosificación , Método Doble Ciego , Femenino , Infecciones por VIH/complicaciones , Hepacivirus/efectos de los fármacos , Hepatitis B/complicaciones , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis C/complicaciones , Humanos , Hígado/efectos de los fármacos , Masculino , Maraviroc , Persona de Mediana Edad , Placebos , Triazoles/administración & dosificación
8.
Curr Opin Infect Dis ; 27(3): 275-81, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24739345

RESUMEN

PURPOSE OF REVIEW: This review describes the impact of HIV infection on gut-associated lymphoid tissue, the mechanisms for persistent gut-associated lymphoid tissue dysfunction despite effective antiretroviral therapy, and potential strategies to restore gut-associated lymphoid tissue function and promote immune reconstitution. RECENT FINDINGS: Recent studies indicate that unresolved microbial translocation and intestinal dysbiosis may continue to promote enteropathy as well as HIV-associated and non-HIV-associated conditions in many HIV patients who otherwise maintain therapeutic control of systemic viral replication. SUMMARY: Several novel therapeutic approaches to reduce intestinal inflammation and mitigate microbial translocation may hold promise for restoring gastrointestinal health and thereby increasing the efficacy of immune reconstitution in HIV-infected patients undergoing antiretroviral therapy.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , Inmunidad Mucosa/inmunología , Mucosa Intestinal/inmunología , Tejido Linfoide/inmunología , Galactosemias , Tracto Gastrointestinal/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Humanos , Inmunidad Mucosa/efectos de los fármacos , Inmunoterapia/métodos , Inflamación/inmunología , Mucosa Intestinal/patología , Activación de Linfocitos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Replicación Viral
9.
HIV Clin Trials ; 15(4): 133-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25143022

RESUMEN

BACKGROUND: In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era. OBJECTIVE: To determine clinical and immunological predictors of death after an OI. METHODS: We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both. RESULTS: The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death. CONCLUSIONS: In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.


Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/mortalidad , Adulto , Femenino , Humanos , Masculino , Análisis Multivariante , Modelos de Riesgos Proporcionales , Factores de Riesgo
10.
Arterioscler Thromb Vasc Biol ; 33(2): 387-92, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23202367

RESUMEN

OBJECTIVE: Mechanisms underlying the cardiovascular risk of lipoprotein(a) are poorly understood. We investigated the relationship of apolipoprotein(a) (apo(a)) size, lipoprotein(a), and allele-specific apo(a) levels with HIV disease activity parameters in a biethnic population. METHODS AND RESULTS: Lipoprotein(a) and allele-specific apo(a) levels were determined in 139 white and 168 black HIV-positive patients. Plasma HIV RNA viral load and CD4+ T-cell count were used as surrogates for disease activity. Lipoprotein(a) and allele-specific apo(a) levels were higher in blacks than whites (for both P<0.001). Apo(a) allele size distribution was similar between the 2 ethnic groups, with a median apo(a) size of 28 kringle 4 repeats. Allele-specific apo(a) levels were positively associated with CD4+ T-cell count (P=0.027) and negatively with plasma HIV RNA viral load (P<0.001). Further, allele-specific apo(a) levels associated with smaller (<28 kringle 4) atherogenic apo(a) sizes were higher in subjects with CD4+ T-cell counts of ≥350 (P=0.002). CONCLUSIONS: Allele-specific apo(a) levels were higher in subjects with high CD4+ T-cell count or low plasma HIV RNA viral load. The findings suggest that HIV disease activity reduced allele-specific apo(a) levels. Higher allele-specific apo(a) levels associated with atherogenic small apo(a) sizes might contribute to increased cardiovascular risk in HIV-positive subjects with improved disease status.


Asunto(s)
Apoproteína(a)/sangre , Infecciones por VIH/sangre , Lipoproteína(a)/sangre , Adulto , Negro o Afroamericano/genética , Apoproteína(a)/genética , Biomarcadores/sangre , Recuento de Linfocito CD4 , California/epidemiología , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etnología , Enfermedades Cardiovasculares/virología , Estudios Transversales , Femenino , VIH/genética , VIH/inmunología , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico , Infecciones por VIH/etnología , Infecciones por VIH/virología , Humanos , Lipoproteína(a)/genética , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Pronóstico , ARN Viral/sangre , Factores de Riesgo , Carga Viral , Población Blanca/legislación & jurisprudencia
12.
J Infect Dis ; 205(9): 1443-7, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22454462

RESUMEN

We investigated whether interferon-inducible genes (IFIGs) with known anti-human immunodeficiency virus (HIV) activity in vitro were associated with in vivo virological response in HIV infection. Nine untreated HIV-1-infected volunteers were treated for 12 weeks with peginterferon alfa-2a. A subset of IFIGs (23 of 47) increased compared with baseline through 6 weeks beyond therapy, and 10 of the 23 IFIGs significantly inversely correlated (r = -0.7; P < .05) with virological response. The strength of peginterferon alfa-2a-induced IFIG response significantly correlated with declines in HIV load during treatment (r(2) = 0.87, p = .003). This study links HIV virological response to a specific IFIG subset, a potential prognostic indicator in peginterferon alfa-2a-treated patients with HIV infection.


Asunto(s)
Antivirales/administración & dosificación , Regulación de la Expresión Génica/efectos de los fármacos , VIH-1/patogenicidad , Interacciones Huésped-Patógeno/genética , Interferón-alfa/administración & dosificación , Polietilenglicoles/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/aislamiento & purificación , Humanos , Leucocitos Mononucleares/metabolismo , ARN Viral/genética , ARN Viral/aislamiento & purificación , Proteínas Recombinantes/administración & dosificación , Carga Viral
13.
J Infect Dis ; 206(11): 1715-23, 2012 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-23002445

RESUMEN

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) reflects an aberrant immune response that can develop in human immunodeficiency virus-infected patients initiating antiretroviral therapy (ART). Its pathogenesis remains unclear. METHODS: We performed a nested case-control study using specimens from ACTG A5164. We compared plasma biomarkers and T-cell subsets in 19 IRIS and 39 control participants at study entry, ART initiation, and IRIS and used conditional logistic regression to develop IRIS predictive models. We evaluated the effect of corticosteroids on biomarker levels. RESULTS: Eleven and 8 participants developed paradoxical and unmasking IRIS, respectively, none while still receiving corticosteroids. Compared to controls, cases displayed elevations at study entry in interleukin (IL) 8, T-helper (Th) 1 (IL-2, interferon [IFN]-γ, tumor necrosis factor [TNF]) and Th17 (IL-17) cytokine levels that persisted through ART initiation and IRIS. In logistic regression, baseline higher IFN-γ and TNF were strong predictors of IRIS. Participants who received corticosteroids and later developed IRIS had marked increases in IL-6, IL-8, and IFN-γ at the time of IRIS. T-cell activation markers did not differ in cases and controls prior to ART but were increased in cases at the time of IRIS. CONCLUSIONS: Increased IL-8, Th1, and Th17 cytokine levels in IRIS patients precede ART initiation and could help identify patient populations at higher risk for IRIS.


Asunto(s)
Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Citocinas/sangre , Infecciones por VIH/tratamiento farmacológico , Síndrome Inflamatorio de Reconstitución Inmune/metabolismo , Interleucina-8/sangre , Adulto , Biomarcadores , Estudios de Casos y Controles , Citocinas/genética , Citocinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Modelos Logísticos , Persona de Mediana Edad , Factores de Riesgo
14.
J Med Virol ; 84(3): 431-7, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22246828

RESUMEN

Peripheral blood mononuclear cells (PBMCs) represent an extrahepatic hepatitis C virus (HCV) reservoir, the significance of which is unclear due to limited studies and varying test methodologies. In this study, a commercial viral load assay for measuring cell-associated PBMC HCV RNA was evaluated. HCV RNA was extracted from PBMCs, sorted CD14+, and CD19+ cells and corresponding plasma samples using the Abbott m2000 and Real-Time HCV assay. Test performance and influence of HIV seropositivity on plasma and PBMC HCV RNA were studied. Among 51 patients, 67 and 62 unique patient samples had detectable plasma and PBMC HCV viral load, respectively. The median PBMC viral load was 535 IU/1 M cells (range 29-5,190). CD19+ cells had significantly higher viral load than CD14+ cells (median log(10) HCV viral load 2.63 vs. 1.50 IU/ml; P< 0.001). Stability of PBMC viral load over time was demonstrated in untreated patients; all patients with an undetectable plasma HCV viral load after HCV treatment also demonstrated undetectable PBMC viral load. Repeated testing in nine samples yielded consistent PBMC viral load, differing by only 1.3-fold (range 1.0-1.7-fold). Among samples with detectable plasma HCV RNA, the correlation between PBMC and plasma viral load was moderate (r = 0.66) and was greater among HCV mono-infected compared to HIV/HCV co-infected subjects (r = 0.80 vs. 0.52). Measurement of cell-associated PBMC HCV RNA using a commercial assay demonstrated promising test characteristics. Differences in PBMC HCV viral load based on HIV-coinfection status and the significance of greater copy number in B-cells requires further study.


Asunto(s)
Coinfección/virología , Hepacivirus/genética , Hepatitis C/virología , Leucocitos Mononucleares/virología , ARN Viral/sangre , Carga Viral/métodos , Adulto , Anciano , Antivirales/farmacología , Antivirales/uso terapéutico , Femenino , Genotipo , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Hepacivirus/efectos de los fármacos , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados
15.
BMC Complement Altern Med ; 12: 84, 2012 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-22747752

RESUMEN

BACKGROUND: Infection with HIV-1 results in marked immunologic insults and structural damage to the intestinal mucosa, including compromised barrier function. While the development of highly active antiretroviral therapy (HAART) has been a major advancement in the treatment of HIV-1 infection, the need for novel complementary interventions to help restore intestinal structural and functional integrity remains unmet. Known properties of pre-, pro-, and synbiotics suggest that they may be useful tools in achieving this goal. METHODS: This was a 4-week parallel, placebo-controlled, randomized pilot trial in HIV-infected women on antiretroviral therapy. A synbiotic formulation (Synbiotic 2000®) containing 4 strains of probiotic bacteria (10(10) each) plus 4 nondigestible, fermentable dietary fibers (2.5 g each) was provided each day, versus a fiber-only placebo formulation. The primary outcome was bacterial translocation. Secondary outcomes included the levels of supplemented bacteria in stool, the activation phenotype of peripheral T-cells and monocytes, and plasma levels of C-reactive protein and soluble CD14. RESULTS: Microbial translocation, as measured by plasma bacterial 16S ribosomal DNA concentration, was not altered by synbiotic treatment. In contrast, the synbiotic formulation resulted in significantly elevated levels of supplemented probiotic bacterial strains in stool, including L. plantarum and P. pentosaceus, with the colonization of these two species being positively correlated with each other. T-cell activation phenotype of peripheral blood lymphocytes showed modest changes in response to synbiotic exposure, with HLA-DR expression slightly elevated on a minor population of CD4+ T-cells which lack expression of HLA-DR or PD-1. In addition, CD38 expression on CD8+ T-cells was slightly lower in the fiber-only group. Plasma levels of soluble CD14 and C-reactive protein were unaffected by synbiotic treatment in this study. CONCLUSIONS: Synbiotic treatment for 4 weeks can successfully augment the levels of probiotic species in the gut during chronic HIV-1 infection. Associated changes in microbial translocation appear to be absent, and markers of systemic immune activation appear largely unchanged. These findings may help inform future studies aimed at testing pre- and probiotic approaches to improve gut function and mucosal immunity in chronic HIV-1 infection. TRIAL REGISTRATION: Clinical Trials.gov: NCT00688311.


Asunto(s)
Bacterias/crecimiento & desarrollo , Traslocación Bacteriana , Colon/microbiología , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Mucosa Intestinal/microbiología , Simbióticos , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Fármacos Anti-VIH/uso terapéutico , Bacterias/genética , Proteína C-Reactiva/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Enfermedad Crónica , Colon/inmunología , Fibras de la Dieta , Heces/microbiología , Femenino , Fermentación , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , Infecciones por VIH/microbiología , Antígenos HLA-DR/metabolismo , Humanos , Mucosa Intestinal/inmunología , Receptores de Lipopolisacáridos/sangre , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Fenotipo , Proyectos Piloto , Prebióticos , Probióticos , Receptor de Muerte Celular Programada 1/metabolismo , ARN Ribosómico 16S/sangre , ARN Ribosómico 16S/genética
16.
Blood ; 113(25): 6304-14, 2009 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-19380868

RESUMEN

Interleukin 7 (IL-7) is a common gamma chain receptor cytokine implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes. The safety and activity of recombinant human IL-7 (rhIL-7) administration were therefore examined in HIV-infected persons. In this prospective randomized placebo-controlled study, a single subcutaneous dose of rhIL-7 was well tolerated with biologic activity demonstrable at 3 microg/kg and a maximum tolerated dose of 30 microg/kg. Injection site reactions and transient elevations of liver function tests were the most notable side effects. Transient increases in plasma HIV-RNA levels were observed in 6 of 11 IL-7-treated patients. Recombinant hIL-7 induced CD4 and CD8 T cells to enter cell cycle; cell-cycle entry was also confirmed in antigen-specific CD8 T cells. Administration of rhIL-7 led to transient down-regulation of the IL-7 receptor alpha chain (CD127) in both CD4(+) and CD8(+) T cells. Single-dose rhIL-7 increased the numbers of circulating CD4(+) and CD8(+) T cells, predominantly of central memory phenotype. The frequency of CD4(+) T cells with a regulatory T-cell phenotype (CD25(high) CD127(low)) did not change after rhIL-7 administration. Thus, rhIL-7 has a biologic and toxicity profile suggesting a potential for therapeutic trials in HIV infection and other settings of lymphopenia. This clinical trial has been registered at http://www.clinicaltrials.gov under NCT0099671.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , VIH-1 , Interleucina-7/uso terapéutico , Subgrupos de Linfocitos T/efectos de los fármacos , Adulto , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ciclo Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Regulación hacia Abajo/efectos de los fármacos , Femenino , Infecciones por VIH/inmunología , Humanos , Memoria Inmunológica/efectos de los fármacos , Interleucina-7/administración & dosificación , Interleucina-7/efectos adversos , Interleucina-7/sangre , Interleucina-7/farmacología , Subunidad alfa del Receptor de Interleucina-7/biosíntesis , Subunidad alfa del Receptor de Interleucina-7/genética , Recuento de Linfocitos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/sangre , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Carga Viral
17.
J Infect Dis ; 201(1): 132-41, 2010 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-19929694

RESUMEN

BACKGROUND: We report composite results from the Merck phase I program of near-consensus clade B human immunodeficiency virus (HIV) type 1 gag vaccines. METHODS: Healthy HIV-uninfected adults were enrolled in 6 blinded placebo-controlled studies evaluating the immunogenicity of (1) a 4-dose regimen of a DNA vaccine, (2) a 3-dose priming regimen of the DNA vaccine with a booster dose of an adenovirus type 5 (Ad5)-vectored vaccine, or (3) a 3-dose regimen of the Ad5 vaccine. The DNA plasmid was provided with or without an aluminum phosphate or CRL1005 adjuvant. The primary end point was the unfractionated HIV-1 gag-specific interferon gamma enzyme-linked immunospot (ELISpot) response 4 weeks after the final dose. RESULTS: Overall, 254 (83%) of 307 subjects randomized to the vaccine groups were evaluable. Adjuvants did not enhance immunogenicity of the DNA vaccine. Postboost ELISpot responder frequencies were higher for Ad5-containing regimens than for the DNA/DNA regimen (33%) but were similar for DNA/Ad5 (55%) and Ad5/Ad5 (50%). DNA/DNA elicited mainly a CD4 response, whereas Ad5/Ad5 elicited mainly a CD8 response; DNA/Ad5 generated CD4 and CD8 responses comparable to those of DNA/DNA and Ad5/Ad5, respectively. CONCLUSIONS: The DNA vaccine alone or as a priming regimen for the Ad5 vaccine did not increase unfractionated ELISpot responses compared with the Ad5 vaccine alone. Qualitative T cell responses to different vaccine regimens deserve further study.


Asunto(s)
Vacunas contra el SIDA/inmunología , ADN Viral/inmunología , Genes gag/inmunología , VIH-1/inmunología , Inmunización Secundaria/métodos , Adenoviridae/inmunología , Adyuvantes Inmunológicos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placebos , Adulto Joven
18.
J Infect Dis ; 201(11): 1686-96, 2010 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-20420510

RESUMEN

BACKGROUND: To our knowledge, the antiviral activity of pegylated interferon alfa-2a has not been studied in participants with untreated human immunodeficiency virus type 1 (HIV-1) infection but without chronic hepatitis C virus (HCV) infection. METHODS: Untreated HIV-1-infected volunteers without HCV infection received 180 microg of pegylated interferon alfa-2a weekly for 12 weeks. Changes in plasma HIV-1 RNA load, CD4(+) T cell counts, pharmacokinetics, pharmacodynamic measurements of 2',5'-oligoadenylate synthetase (OAS) activity, and induction levels of interferon-inducible genes (IFIGs) were measured. Nonparametric statistical analysis was performed. RESULTS: Eleven participants completed 12 weeks of therapy. The median plasma viral load decrease and change in CD4(+) T cell counts at week 12 were 0.61 log(10) copies/mL (90% confidence interval [CI], 0.20-1.18 log(10) copies/mL) and -44 cells/microL (90% CI, -95 to 85 cells/microL), respectively. There was no correlation between plasma viral load decreases and concurrent pegylated interferon plasma concentrations. However, participants with larger increases in OAS level exhibited greater decreases in plasma viral load at weeks 1 and 2 (r = -0.75 [90% CI, -0.93 to -0.28] and r = -0.61 [90% CI, -0.87 to -0.09], respectively; estimated Spearman rank correlation). Participants with higher baseline IFIG levels had smaller week 12 decreases in plasma viral load (0.66 log(10) copies/mL [90% CI, 0.06-0.91 log(10) copies/mL]), whereas those with larger IFIG induction levels exhibited larger decreases in plasma viral load (-0.74 log(10) copies/mL [90% CI, -0.93 to -0.21 log(10) copies/mL]). CONCLUSION: Pegylated interferon alfa-2a was well tolerated and exhibited statistically significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein levels (weeks 1 and 2) and IFIG induction levels (week 12) but not with pegylated interferon concentrations.


Asunto(s)
Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Interferón-alfa/efectos adversos , Interferón-alfa/uso terapéutico , Polietilenglicoles/efectos adversos , Polietilenglicoles/uso terapéutico , 2',5'-Oligoadenilato Sintetasa/metabolismo , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Recuento de Linfocito CD4 , Perfilación de la Expresión Génica , Infecciones por VIH/virología , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/farmacocinética , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , ARN Viral/sangre , Proteínas Recombinantes , Resultado del Tratamiento , Carga Viral
19.
Lancet HIV ; 8(7): e397-e407, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34197772

RESUMEN

BACKGROUND: In DISCOVER, a multinational, randomised controlled trial, emtricitabine and tenofovir alafenamide compared with emtricitabine and tenofovir disoproxil fumarate showed non-inferior efficacy for HIV prevention and improved bone mineral density and renal safety biomarkers at week 48. We report outcomes analysed after all participants had completed 96 weeks of follow-up. METHODS: This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in Europe and North America. Adult cisgender men and transgender women who have sex with men, both with a high risk of acquiring HIV as determined by self-reported sexual behaviour or recent sexually transmitted infections, were randomly assigned (1:1) to receive either emtricitabine and tenofovir alafenamide (200/25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine and tenofovir disoproxil fumarate (200/300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). The primary efficacy outcome was incident HIV infection. Incidence of HIV-1 infection per 100 person-years was assessed when the last participant had completed 96 weeks of follow-up. This trial is registered with ClinicalTrials.gov, number NCT02842086. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5387 participants were randomly assigned to receive emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693), contributing 10 081 person-years of follow-up. At 96 weeks of follow-up, there were eight HIV infections in participants who had received emtricitabine and tenofovir alafenamide (0·16 infections per 100 person-years [95% CI 0·07-0·31]) and 15 in participants who had received emtricitabine and tenofovir disoproxil fumarate (0·30 infections per 100 person-years [0·17-0·49]). Emtricitabine and tenofovir alafenamide maintained its non-inferiority to emtricitabine and tenofovir disoproxil fumarate for HIV prevention (IRR 0·54 [95% CI 0·23-1·26]). Approximately 78-82% of participants reported taking study medication more than 95% of the time across all study visits. Rates of sexually transmitted infections remained high and similar across groups (21 cases per 100 person-years for rectal gonorrhoea and 28 cases per 100 person-years for rectal chlamydia). Emtricitabine and tenofovir alafenamide continued to show superiority over emtricitabine and tenofovir disoproxil fumarate in all but one of the six prespecified bone mineral density and renal biomarkers. There was more weight gain among participants who had received emtricitabine and tenofovir alafenamide (median weight gain 1·7 kg vs 0·5 kg, p<0·0001). INTERPRETATION: Emtricitabine and tenofovir alafenamide is safe and effective for longer-term pre-exposure prophylaxis in cisgender men and transgender women who have sex with men. FUNDING: Gilead Sciences.


Asunto(s)
Adenina/análogos & derivados , Alanina/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/prevención & control , Organofosfonatos/uso terapéutico , Tenofovir/uso terapéutico , Adenina/efectos adversos , Adenina/uso terapéutico , Adulto , Anciano , Alanina/efectos adversos , Fármacos Anti-VIH/efectos adversos , Método Doble Ciego , Quimioterapia Combinada/efectos adversos , Emtricitabina/efectos adversos , Femenino , Estudios de Seguimiento , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , Organofosfonatos/efectos adversos , Profilaxis Pre-Exposición , Tenofovir/efectos adversos , Resultado del Tratamiento , Adulto Joven
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