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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.
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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 JovenRESUMEN
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.
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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 , PermeabilidadRESUMEN
INTRODUCTION: Guidelines advocate the treatment of HCV in all HIV/HCV co-infected individuals. The aim of this randomized, open-label study (ClinicalTrials.gov identifier: NCT02707601; https://clinicaltrials.gov/ct2/show/NCT02707601) was to evaluate the safety/efficacy of ledipasvir/sofosbuvir (LDV/SOF) co-administered with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or rilpivirine/F/TAF (R/F/TAF) in HIV-1/HCV co-infected participants. METHODS: Participants with HIV-1 RNA <50 copies/mL and chronic HCV-genotype (GT) 1 (HCV treatment-naïve ± compensated cirrhosis or HCV treatment-experienced non-cirrhotic) were randomized 1:1 to switch to E/C/F/TAF or R/F/TAF. If HIV suppression was maintained at Week 8, participants received 12 weeks of LDV/SOF. The primary endpoint was sustained HCV virologic response 12 weeks after LDV/SOF completion (SVR12). RESULTS: Of 150 participants, 148 received ≥1 dose of HIV study drug and 144 received LDV/SOF (72 in each F/TAF group; 83% GT1a, 94% HCV treatment-naïve, 12% cirrhotic). Overall, SVR12 was 97% (95% confidence interval: 93-99%). Black race did not affect SVR12. Of four participants not achieving SVR12, one had HCV relapse, one had HCV virologic non-response due to non-adherence, and two missed the post-HCV Week 12 visit. Of 148 participants, 96% receiving E/C/F/TAF and 95% receiving R/F/TAF maintained HIV suppression at Week 24; no HIV resistance was detected. No participant discontinued LDV/SOF or E/C/F/TAF due to adverse events; one participant discontinued R/F/TAF due to worsening of pre-existing hypercholesterolemia. Renal toxicity was not observed in either F/TAF regimen during LDV/SOF co-administration. In conclusion, high rates of HCV SVR12 and maintenance of HIV suppression were achieved with LDV/SOF and F/TAF-based regimens. CONCLUSION: This study supports LDV/SOF co-administered with an F/TAF-based regimen in HIV-1/HCV-GT1 co-infected patients.
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Coinfección/tratamiento farmacológico , Combinación de Medicamentos , Infecciones por VIH/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Adenina/administración & dosificación , Adenina/análogos & derivados , Adulto , Anciano , Alanina , Bencimidazoles/administración & dosificación , Coinfección/virología , Farmacorresistencia Viral/efectos de los fármacos , Emtricitabina/administración & dosificación , Femenino , Fluorenos/administración & dosificación , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/patogenicidad , Hepacivirus/patogenicidad , Hepatitis C/complicaciones , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/aislamiento & purificación , Sofosbuvir/administración & dosificación , Tenofovir/administración & dosificaciónRESUMEN
BACKGROUND: We aimed to characterize the impact of antiretroviral therapy (ART) initiation on gastrointestinal-associated lymphoid tissue at various sites along the gastrointestinal site. METHODOLOGY: Peripheral blood and duodenal and rectal biopsies were obtained from 12 HIV to 33 treatment-naive HIV participants at baseline and after 9 months ART. Tissue was digested for immunophenotyping. Inflammatory, bacterial translocation and intestinal damage markers were measured in plasma. RESULTS: Twenty-six HIV patients completed follow-up. The lowest reconstitution of CD4 T cells and the lowest CD4/CD8 ratio during ART compared with blood were observed in the duodenum with the rectum being either intermediate or approaching blood levels. Regulatory T cells were in higher proportions in the duodenum than the rectum and neither declined significantly during ART. Several correlations with biomarkers of microbial translocation were observed including increases in lipoteichoic acid levels, which reflects Gram-positive bacterial translocation, correlated with increases in %CD4 T cells in the duodenum (Rho 0.773, Pâ=â0.033), and with decreases in duodenal regulatory T-cell populations (Rho -0.40, Pâ=â0.045). CONCLUSION: HIV-mediated immunological disruption is greater in the duodenum than rectum and blood before and during ART. Small intestine damage may represent a unique environment for T-cell depletion, which might be attenuated by interaction with Gram-positive bacteria.
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Duodeno/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Reconstitución Inmune , Recto/inmunología , Adulto , Terapia Antirretroviral Altamente Activa , Biopsia , Sangre/inmunología , Relación CD4-CD8 , Linfocitos T CD4-Positivos/inmunología , Femenino , Humanos , Inmunofenotipificación , Mucosa Intestinal/inmunología , Modelos Lineales , Activación de Linfocitos , MasculinoRESUMEN
BACKGROUND: Systemic inflammation persists in chronic HIV infection and is associated with increased rates of non-AIDS events such as cardiovascular and liver disease. Increased gut permeability and systemic exposure to microbial products are key drivers of this inflammation. Serum-derived bovine immunoglobulin/protein isolate (SBI) supports gut healing in other conditions such as inflammatory bowel disease. METHODS: In this randomized, double-blind study, participants receiving suppressive antiretroviral therapy (ART) with chronic diarrhea received placebo or SBI at 2.5 g BID or 5 g BID for 4 weeks, followed by a 20-week placebo-free extension phase with SBI at either 2.5 or 5 g BID. Intestinal fatty acid binding protein (I-FABP), zonulin, flagellin, lipopolysaccharide (LPS) and LPS-binding protein, and inflammatory markers were measured by ELISA or multiplex assays. Non-parametric tests were used for analysis. RESULTS: One hundred three participants completed the study. By week 24 SBI significantly decreased circulating levels of I-FABP (-0.35 ng/µL, P=0.002) and zonulin (-4.90 ng/µL, P=0.003), suggesting improvement in gut damage, and interleukin-6 (IL-6) (-0.40 pg/µL, P=0.002), reflecting improvement in systemic inflammation. In participants with the lowest quartile of CD4+ T-cell counts at baseline (189-418 cells/µL), CD4+ T-cell counts increased significantly (26 cells/µL; P=0.002). CONCLUSIONS: Oral SBI may decrease inflammation and warrants further exploration as a potential strategy to improve gut integrity and decrease systemic inflammation among persons receiving prolonged suppressive ART.
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BACKGROUND & AIMS: Nutritional deficiency and inflammation may impact CD4+ T cell recovery during combination antiretroviral therapy (cART), particularly in resource-limited settings where malnutrition is prevalent. The aim of this study was to investigate the relationship of micronutrient and inflammation biomarkers to CD4 recovery after cART initiation. METHODS: We conducted a secondary analysis of a random sub-cohort sample (n = 270) from a multinational randomized trial of cART regimen efficacy among 1571 cART-naïve adults. We measured pre-cART serum levels of micronutrients (Vitamin A, B6, B12, D, total carotenoids, selenium, and iron) and inflammation (C-reactive protein, soluble CD14 (sCD14), IFNγ, TNFα, Interleukin-6, and C-X-C motif chemokine 10 (CXCL10/IP10), EndoCab (IgM)) biomarkers. Biomarker status (i.e. micronutrient deficiency vs. sufficiency and elevated vs. low inflammation) was defined using established cutoffs or quartiles. Mixed-effects linear regression models were used to determine the association of baseline (pre-cART) concentrations of individual biomarkers with CD4 recovery through 96 weeks post-cART initiation. RESULTS: In models adjusting for time-dependent viral load and baseline CD4 count, age, sex, body mass index, country, treatment regimen, anemia and hypoalbuminemia status, pre-cART vitamin D deficiency was associated with lower CD4 recovery (-14.9 cells/mm3, 95% CI: -27.9, -1.8) compared to sufficiency. In contrast, baseline selenium deficiency (20.8 cells/mm3, 95% CI: 3.3, 38.3), vitamin A deficiency (35.9 cells/mm3, 95% CI: 17.6, 54.3) and high sCD14 (23.4 cells/mm3, 95% CI: 8.9, 37.8) were associated with higher CD4 recovery compared to sufficient/low inflammation status. CONCLUSIONS: In summary, baseline vitamin D deficiency was associated with diminished CD4 recovery after cART initiation; impaired CD4 recovery may contribute to the poor clinical outcomes recently observed in individuals with vitamin D deficiency. Vitamin A, selenium and sCD14 were associated with CD4 recovery but future studies are needed to further explore these relationships.
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Linfocitos T CD4-Positivos/fisiología , Infecciones por VIH , Inflamación , Desnutrición , Micronutrientes/sangre , Adulto , Antirretrovirales/uso terapéutico , Estudios de Cohortes , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/fisiopatología , Humanos , Inflamación/complicaciones , Inflamación/fisiopatología , Masculino , Desnutrición/complicaciones , Desnutrición/fisiopatología , Estado Nutricional/fisiología , Selenio/sangre , Resultado del Tratamiento , Vitamina A/sangre , Vitamina D/sangreRESUMEN
Objectives To evaluate serum-derived bovine immunoglobulin/protein isolate (SBI) for safety and impact on gastrointestinal (GI) symptoms in HIV patients with chronic idiopathic diarrhea. Methods A multi-center trial comprised of a double-blind, placebo (PBO)-controlled lead-in phase, (participants received PBO or SBI at 2.5 or 5.0 g BID for 4 weeks) followed by a 20-week, PBO-free phase (SBI at either 2.5 or 5.0 g BID). Participants included HIV-infected patients who were virologically suppressed with a history of chronic idiopathic diarrhea, defined as > 3 loose stools per day for ≥ 3 months without an identifiable cause. Safety was evaluated by monitoring adverse events (AEs) and clinical laboratory testing. Health status and changes in GI symptoms were assessed using validated questionnaires. Results SBI was well tolerated by the 103 participants with only 2 withdrawals due to AEs potentially associated with SBI. Mean number of daily unformed stools decreased from about 4 at baseline to less than 2 by week 4 for all study groups. Improvements in several other GI symptoms were also reported. Comparison of the PBO group to SBI groups showed no significant differences, although both SBI cohorts reported significantly improved health status scores. GI symptom improvements were maintained throughout the 20-week PBO-free phase. Conclusions Oral SBI is safe and well tolerated at the doses studied in HIV patients with chronic diarrhea. No conclusions could be drawn regarding impact on GI symptoms. Additional studies are ongoing to examine the biological and immunologic effects of SBI in virologically suppressed HIV-infected patients.
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Diarrea/tratamiento farmacológico , Infecciones por VIH/complicaciones , Inmunoglobulinas/administración & dosificación , Factores Inmunológicos/administración & dosificación , Administración Oral , Adulto , Anciano , Animales , Bovinos , Enfermedad Crónica/tratamiento farmacológico , Estudios Cruzados , Diarrea/patología , Método Doble Ciego , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Inmunoglobulinas/efectos adversos , Inmunoglobulinas/aislamiento & purificación , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/aislamiento & purificación , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Estudios Prospectivos , Suero/química , Resultado del TratamientoRESUMEN
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.
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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 , HumanosRESUMEN
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.
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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 & dosificaciónRESUMEN
[This corrects the article DOI: 10.1371/journal.ppat.1005381.].
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BACKGROUND: In the primary 48-week analysis of a hepatic safety trial in patients with HIV-1 coinfected with HBV and/or HCV, maraviroc-containing treatment regimens were not associated with increased hepatotoxicity. METHODS: In this randomized, double-blind, placebo-controlled, multicentre study, patients received maraviroc twice daily (n=70) or placebo (n=67) with concomitant antiretroviral therapy for 144 weeks (Clinicaltrials.gov identifier, NCT01327547). The primary end point was the proportion of patients with protocol-defined Grade 3/4 alanine aminotransferase (ALT) abnormalities through week 48. Key secondary end points included 144-week analysis of Grade 3/4 ALT abnormalities and liver fibrosis by enhanced liver fibrosis (ELF) testing, hepatic elastography and an optional biopsy substudy. RESULTS: Through 144 weeks of treatment, two (maraviroc) and three (placebo) patients met the protocol-defined Grade 3/4 ALT end point. Similar to the 48-week results, there were no statistically significant differences between groups in change from baseline in ELF or hepatic elastography. However, decreased elastography scores were noted in the maraviroc group. Blinded pathologist review suggested that 2 of 11 paired biopsies (both on maraviroc) showed signs of decreased fibrosis. One (maraviroc) and two (placebo) patients experienced treatment-related hepatobiliary adverse events (AEs). Five patients in the maraviroc group discontinued because of treatment-related AEs versus three in the placebo group. One death in the maraviroc group and two deaths in the placebo group were reported. CONCLUSIONS: Use of maraviroc did not increase hepatotoxicity in this population through 144 weeks. Further investigation regarding possible beneficial effects of maraviroc on liver fibrosis may be warranted.
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Coinfección , Ciclohexanos/efectos adversos , Inhibidores de Fusión de VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Hepatitis B , Hepatitis C , Hígado/efectos de los fármacos , Triazoles/efectos adversos , Adulto , Anciano , Terapia Antirretroviral Altamente Activa/efectos adversos , Ciclohexanos/uso terapéutico , Femenino , Inhibidores de Fusión de VIH/uso terapéutico , Infecciones por VIH/metabolismo , Hepatitis B/virología , Hepatitis C/virología , Humanos , Hígado/metabolismo , Hígado/patología , Hígado/virología , Pruebas de Función Hepática , Masculino , Maraviroc , Persona de Mediana Edad , Resultado del Tratamiento , Triazoles/uso terapéutico , Carga ViralRESUMEN
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.
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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 , ZimbabweRESUMEN
BACKGROUND: The genomic heterogeneity of HIV-1 impedes the ability of consensus sequences in vaccines to elicit effective antiviral immune responses. AGS-004 amplifies translation-competent RNA molecules encoding for Gag, Rev, Vpr, and Nef from the patient's autologous virus and loads them into dendritic cells. METHODS: This phase IIB, multicenter, 2:1 randomized, double-blind, placebo-controlled study enrolled 54 HIV-1-infected patients on antiretroviral therapy with viral loads (VLs) <50 copies per milliliter, current CD4 T-cell counts >450 cells per cubic millimeter, and nadir counts >200 cells per cubic millimeter, to receive intradermal injections of study product into the axillary lymph node region every 4 weeks. At week 16, a 12-week analytical treatment interruption (ATI) was undertaken. RESULTS: There was no difference in the end-of-ATI VL (average of values from weeks 11 and 12) between the 2 arms of the study [4.39 (4.17, 4.69) vs. 4.47 (3.76, 4.64) log10 HIV-1 RNA; P = 0.73]. Between arms, no change between pre-antiretroviral therapy VL and the end-of-ATI VL [-0.06 (0.24, -0.32) vs. -0.17 (0.17, -0.32) log10 HIV-1 RNA; P = 0.43] was observed. When interferon-γ, interleukin-2, tumor necrosis factor α, CD107a, and granzyme b expressions were measured by multicolor flow cytometry, a greater percentage of AGS-004 than of placebo recipients had multifunctional cytotoxic T-lymphocyte responses induced in the CD28+/CD45RA-CD8 effector/memory T-cell population to dendritic cells electroporated with autologous antigens. Adverse events consisted of transient, mild (grade 1) local injection site reactions. CONCLUSIONS: Despite the induction of HIV-specific effector/memory CD8 T-cell responses, no antiviral effect was seen after the administration of AGS-004 when compared with placebo.
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Células Dendríticas/inmunología , Infecciones por VIH/terapia , VIH-1/inmunología , Inmunoterapia/métodos , ARN Viral/uso terapéutico , Linfocitos T Citotóxicos/inmunología , Adolescente , Adulto , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Método Doble Ciego , Femenino , Granzimas/biosíntesis , VIH-1/genética , Humanos , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Proteína 1 de la Membrana Asociada a los Lisosomas/biosíntesis , Masculino , Persona de Mediana Edad , Placebos/uso terapéutico , Factor de Necrosis Tumoral alfa/biosíntesis , Carga Viral , Adulto Joven , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen rev del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen vpr del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
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.
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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 & dosificaciónRESUMEN
INTRODUCTION: Novel approaches are urgently needed to achieve the next level of control of HIV infection beyond antiretroviral medications that will lead to the ultimate goal of curing HIV infection. Exploiting the innate immune system control of HIV is one possible component of that strategy with pegylated interferon α representing a well-characterized agent that is being applied to this effort. AREAS COVERED: In this review, the authors summarize the history of interferon α treatment in the setting of HIV infection with a focus on clinical trials that examined the downstream effects on innate immune responses. More recently, clinical trials that administered pegylated interferon α-2a have demonstrated which interferon-stimulated genes are associated with its antiviral effects and which of these host-restriction factors may play a role in limiting the magnitude of the HIV reservoir. EXPERT OPINION: The potential to exploit interferon α as part of a cure strategy is provocative. Whether key interferon-induced antiviral factors can be upregulated sufficiently to affect the reservoir is unknown. Additional research employing pegylated interferon α-2a is needed to identify which innate immune pathways are candidate targets for novel biological therapies for the potential cure of HIV infection.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Animales , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Antivirales/farmacología , Infecciones por VIH/virología , Humanos , Inmunidad Innata/efectos de los fármacos , Interferón-alfa/farmacología , Polietilenglicoles/farmacología , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéuticoRESUMEN
OBJECTIVE: This study was aimed to correlate in vivo interferon (IFN) inducible gene (IFIG) expression and IFIG induction with viral-load (VL) and VL-kinetics of Human-Immunodeficiency-Virus (HIV) or Hepatitis-C-Virus (HCV) in HIV-positive patients treated with pegylated IFN-alpha-2a (PegIFNα). METHODS: HIV mono-infected patients (N=8) and HIV/HCV co-infected patients (N=23, without HIV-viremia) were treated with PegIFNα (180 µg/week) for 12 and 48 weeks, respectively. Blood sampling for monitoring IFIG expression occurred at day_0 and week_3, _6 and _12 for HIV mono-infected patients vs. only at day_0 and week_48 for HIV/HCV co-infected subjects. IFIG expression (N=20) was measured in peripheral blood mononuclear cells by bDNA-assay. VL levels/changes in plasma were analyzed for correlation with IFIG expression/induction at/between selected time points. Overall, P<0.05 was considered significant. RESULTS: None of the 20 IFIG expression profiles at day_0 correlated significantly with HIV-VL at day_0. Expression at day_0 of 3 IFIG (APOBEC3G/OAS1/OAS2) correlated significantly (r>+0.42/P<0.05) with HCV-VL at day_0. The strongest antiviral effect [measured as median viral decline per week: ΔVL/week (log10)] occurred in common against HIV and HCV between day_0 and week_3 during 12 weeks of continuous PegIFNα treatment in both cohorts. Expression at day_0 of 1 IFIG (APOBEC3A) correlated significantly (r<-0.71/P<0.05) with HIV-ΔVL/week (log10) from day_0 to week_3. No significance was reached in correlations between expression values of 20 IFIG at day_0 and HCV-ΔVL/week (log10) from day_0 to week_3. No significant correlation was detected between IFIG expression changes (ΔIFIG=induction) from day_0 to week_3 and HIV-ΔVL/week (log10) from day_0 to week_3. Interestingly, induction of 1 IFIG (ΔISG20) from day_0 to week_48 was significantly associated (P<0.05) with permanent HCV clearance. CONCLUSION: This study demonstrates the differential specificity of PegIFNα mediated molecular actions by dissecting the kinetics of IFIG expression and induction, suggesting multiple, possibly non-overlapping mechanisms for antiviral effects against HCV and HIV.
RESUMEN
BACKGROUND: Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore, some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. METHODS: A case-cohort study (n = 470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings clinical trial (1571 HIV treatment-naive adults who initiated cART; CD4 T-cell count <300 cells/mm; 9 countries) was conducted. A subcohort of 30 participants per country was randomly selected; additional cases were added from the main cohort. Cases [n = 236 (random subcohort 36; main cohort 200)] had clinical progression (incident WHO stage 3/4 event or death) within 96 weeks after cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. RESULTS: Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4 T-cell count was 167 cells per cubic millimeter. In multivariate analysis, highest quartile C-reactive protein concentration [adjusted hazard ratio (aHR), 2.53; 95% confidence interval (CI): 1.02 to 6.28] and CD4 T-cell activation (aHR, 5.18; 95% CI: 1.09 to 24.47) were associated with primary outcomes, compared with lowest quartiles. sCD14 had a trend toward association with clinical failure (aHR, 2.24; 95% CI: 0.96 to 5.21). CONCLUSIONS: Measuring C-reactive protein and CD4 T-cell activation may identify patients with CD4 T-cell counts <300 cells per cubic millimeter at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Proteína C-Reactiva/metabolismo , Linfocitos T CD4-Positivos/fisiología , Infecciones por VIH/metabolismo , Infecciones por VIH/patología , Adulto , Fármacos Anti-VIH/administración & dosificación , Biomarcadores , Recuento de Linfocito CD4 , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Humanos , Internacionalidad , MasculinoRESUMEN
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 48âweeks 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 & dosificaciónRESUMEN
OBJECTIVE: To investigate the potential role of mucosal intestinal myofibroblasts (IMFs) in HIV and associated fibrosis in gut-associated lymphoid tissue. DESIGN: Profibrotic changes within the secondary lymphoid organs and mucosa have been implicated in failed immune reconstitution following effective combination antiretroviral therapy (cART). Microbial translocation is believed to be sustaining these systemic inflammatory pathways. IMFs are nonprofessional antigen-presenting cells with both immunoregulatory and mesenchymal functions that are ideally positioned to respond to translocating microbial antigen. METHODS: Duodenal biopsies, obtained from patients naive to cART, underwent trichrome staining and were examined for tissue growth factor-beta (TGF-ß) expression. Combined immunostaining and second harmonic generation analysis were used to determine IMF activation and collagen deposition. Confocal microscopy was performed to examine IMF activation and Toll-like receptor (TLR)4 expression. Finally, primary IMF cultures were stimulated with lipopolysaccharide to demonstrate the expression of the inflammatory biomarkers. RESULTS: The expression of the fibrosis-promoting molecule, TGF-ß1, is significantly increased in duodenal biopsies from HIV patients naïve to cART, and negatively correlated with subsequent peripheral CD4(+) recovery. The increase in TGF-ß1 coincided with an increase in collagen deposition in the duodenal mucosa in the tissue area adjacent to the IMFs. We also observed that IMFs expressed TLR4 and had an activated phenotype since they were positive for fibroblast activation protein. Finally, stimulation of IMFs from HIV patients with TLR4 resulted in significantly increased expression of profibrotic molecules, TGF-ß1, and interleukin-6. CONCLUSION: Our data support the hypothesis that activated IMFs may be among the major cells contributing to the profibrotic changes, and thus, the establishment and maintenance of systemic inflammation interfering with immune reconstitution in HIV patients.