RESUMEN
BACKGROUND: Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events. METHODS: This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sß-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed. FINDINGS: Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001). INTERPRETATION: Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials. FUNDING: Bayer Pharmaceuticals.
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Anemia de Células Falciformes , Hipertensión , Proteinuria , Pirazoles , Pirimidinas , Humanos , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/complicaciones , Masculino , Femenino , Método Doble Ciego , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Adulto , Pirimidinas/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/administración & dosificación , Hipertensión/tratamiento farmacológico , Proteinuria/tratamiento farmacológico , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Sickle cell disease (SCD) is characterized by hemolysis, vaso-occlusion, and ischemia. HIV-1 infection was previously shown to be suppressed in SCD PBMCs. Here, we report that HIV-1 suppression is attributed to the increased expression of iron, hypoxia, and interferon-induced innate antiviral factors. Inhibition of upregulated antiviral genes, HMOX-1, CDKN1A, and CH25H, increased HIV-1 replication in SCD PBMCs, suggesting their critical role in HIV-1 suppression. Levels of IFN-ß were elevated in SCD patients. Sickle cell hemoglobin (HbS) treatment of THP-1-derived and primary monocyte-derived macrophages induced production of IFN-ß, upregulated antiviral gene expression, and suppressed HIV-1 infection. Infection with mouse-adapted EcoHIV was suppressed in the SCD mice that also exhibited elevated levels of antiviral restriction factors. Our findings suggest that hemolysis and release of HbS leads to the induction of IFN-ß production, induction of cellular antiviral state by the expression of iron and IFN-driven factors, and suppression of HIV-1 infection.
RESUMEN
The efficacy and safety of rivipansel, a predominantly E-selectin antagonist, were studied in a phase 3, randomized, controlled trial for vaso-occlusive crisis (VOC) requiring hospitalization (RESET). A total of 345 subjects (204 adults and 141 children) were randomized and 320 were treated (162 with rivipansel, 158 with placebo) with an IV loading dose, followed by up to 14 additional 12-hourly maintenance doses of rivipansel or placebo, in addition to standard care. Rivipansel was similarly administered during subsequent VOCs in the Open-label Extension (OLE) study. In the full analysis population, the median time to readiness for discharge (TTRFD), the primary end point, was not different between rivipansel and placebo (-5.7 hours, P = .79; hazard ratio, 0.97), nor were differences seen in secondary end points of time to discharge (TTD), time to discontinuation of IV opioids (TTDIVO), and cumulative IV opioid use. Mean soluble E-selectin decreased 61% from baseline after the loading dose in the rivipansel group, while remaining unchanged in the placebo group. In a post hoc analysis, early rivipansel treatment within 26.4 hours of VOC pain onset (earliest quartile of time from VOC onset to treatment) reduced median TTRFD by 56.3 hours, reduced median TTD by 41.5 hours, and reduced median TTDIVO by 50.5 hours, compared with placebo (all P < .05). A similar subgroup analysis comparing OLE early-treatment with early-treatment RESET placebo showed a reduction in TTD of 23.1 hours (P = .062) and in TTDIVO of 30.1 hours (P = .087). Timing of rivipansel administration after pain onset may be critical to achieving accelerated resolution of acute VOC. Trial Registration: Clinicaltrials.gov, NCT02187003 (RESET), NCT02433158 (OLE).
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Anemia de Células Falciformes , Hemoglobinopatías , Compuestos Orgánicos Volátiles , Adulto , Niño , Humanos , Selectina E/uso terapéutico , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Compuestos Orgánicos Volátiles/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/etiología , Analgésicos Opioides/uso terapéutico , Método Doble CiegoRESUMEN
Patients with sickle cell disease (SCD) have a lower risk for HIV-1 infection. We reported restriction of ex vivo HIV-1 infection in SCD peripheral blood mononuclear cells (PBMCs) that was due, in part, to the upregulation of antiviral, inflammatory, and hemolytic factors, including heme oxygenase-1 (HO-1). Here, we investigated whether individuals with sickle cell trait (SCT), who develop mild hemolysis, also restrict HIV-1 infection. Ex vivo infection of SCT PBMCs exhibited an approximately twofold reduction of HIV-1 replication and lower levels of HIV-1 reverse transcription products, 2-long terminal repeat circle, HIV-1 integration, and gag RNA expression. SCT PBMCs had higher HO-1 messenger RNA (mRNA) and protein levels and reduced ribonucleotide reductase 2 (RNR2) protein levels. HO-1 inhibition by tin porphyrin eliminated ex vivo HIV-1 restriction. Among Howard University clinic recruits, higher levels of HO-1 and RNR2 mRNA and lower HIV-1 env mRNA levels were found in SCT individuals living with HIV-1. To determine the population-level effect of SCT on HIV-1 prevalence, we assessed SCT among women living with HIV (WLH) in the WIHS (Women Interagency HIV-1 Study). Among WIHS African-American participants, the prevalence of SCT was lower among women with HIV compared with uninfected women (8.7% vs 14.2%; odds ratio, 0.57; 95% confidence interval, 0.36-0.92; P = .020). WIHS WLH with SCT had higher levels of CD4+/CD8+ ratios over 20 years of follow-up (P = .003) than matched WLH without SCT. Together, our findings suggest that HIV-1 restriction factors, including HO-1 and RNR2, might restrict HIV-1 infection among individuals with SCT and limit the pathogenicity of HIV.
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Anemia de Células Falciformes , Infecciones por VIH , VIH-1 , Rasgo Drepanocítico , Anemia de Células Falciformes/epidemiología , Femenino , Infecciones por VIH/epidemiología , Humanos , Leucocitos Mononucleares , Rasgo Drepanocítico/genéticaRESUMEN
INTRODUCTION: Chronic kidney disease (CKD) is a prevalent complication of sickle cell anemia (SCA). Hyperfiltration that delayed detection of CKD is common in SCA patients. Identification of novel urinary biomarkers correlating with glomerular filtration rates may help to detect and predict progression of renal disease. METHODS: Reanalysis of mass spectra of urinary samples obtained from University of Illinois at Chicago identified kringle domain-containing protein HGFL. RESULTS: HGFL levels correlated with hyperfiltration, were significantly reduced at CKD stage 1 compared to stage 0, negatively correlated with progression of CKD and were suitable for differentiation of stage 1. Better prediction of CKD progression to stage 2 was observed for HGFL-based risk prediction compared to the estimated glomerular filtration rate (eGFR)-based prediction. Results from a Howard University patient cohort supported the utility of HGFL-based test for the differentiation of stage 1 of CKD. CONCLUSION: Urinary HGFL may contribute additional information beyond eGFR and improve diagnosis of early-stage CKD in SCA patients.
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Anemia de Células Falciformes/complicaciones , Factor de Crecimiento de Hepatocito/orina , Proteínas Proto-Oncogénicas/orina , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/orina , Adolescente , Adulto , Anciano , Biomarcadores/orina , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Tasa de Filtración Glomerular , Factor de Crecimiento de Hepatocito/química , Humanos , Kringles , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas/química , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/fisiopatología , Adulto JovenAsunto(s)
Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/orina , Orosomucoide/metabolismo , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/orina , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Orosomucoide/orina , Adulto JovenRESUMEN
In the US, mortality in sickle cell disease (SCD) increases after age 18-20 years. Biomarkers of mortality risk can identify patients who need intensive follow-up and early or novel interventions. We prospectively enrolled 510 SCD patients aged 3-20 years into an observational study in 2006-2010 and followed 497 patients for a median of 88 months (range 1-105). We hypothesized that elevated pulmonary artery systolic pressure as reflected in tricuspid regurgitation velocity (TRV) would be associated with mortality. Estimated survival to 18 years was 99% and to 25 years, 94%. Causes of death were known in seven of 10 patients: stroke in four (hemorrhagic two, infarctive one, unspecified one), multiorgan failure one, parvovirus B19 infection one, sudden death one. Baseline TRV ≥2.7 m/second (>2 SD above the mean in age-matched and gender-matched non-SCD controls) was observed in 20.0% of patients who died vs 4.6% of those who survived (P = .012 by the log rank test for equality of survival). The baseline variable most strongly associated with an elevated TRV was a high hemolytic rate. Additional biomarkers associated with mortality were ferritin ≥2000 µg/L (observed in 60% of patients who died vs 7.8% of survivors, P < .001), forced expiratory volume in 1 minute to forced vital capacity ratio (FEV1/FVC) <0.80 (71.4% of patients who died vs 18.8% of survivors, P < .001), and neutrophil count ≥10x109 /L (30.0% of patients who died vs 7.9% of survivors, P = .018). In SCD children, adolescents and young adults, steady-state elevations of TRV, ferritin and neutrophils and a low FEV1/FVC ratio may be biomarkers associated with increased risk of death.
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Anemia de Células Falciformes , Insuficiencia de la Válvula Tricúspide , Adolescente , Adulto , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/mortalidad , Anemia de Células Falciformes/fisiopatología , Biomarcadores/sangre , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Ferritinas/sangre , Estudios de Seguimiento , Humanos , Recuento de Leucocitos , Masculino , Neutrófilos , Estudios Prospectivos , Tasa de Supervivencia , Insuficiencia de la Válvula Tricúspide/sangre , Insuficiencia de la Válvula Tricúspide/etiología , Insuficiencia de la Válvula Tricúspide/mortalidad , Insuficiencia de la Válvula Tricúspide/fisiopatología , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Direct-acting antiviral inhibitors have revolutionized the treatment of hepatitis C virus (HCV) infected patients. Herein is described the discovery of velpatasvir (VEL, GS-5816), a potent pan-genotypic HCV NS5A inhibitor that is a component of the only approved pan-genotypic single-tablet regimens (STRs) for the cure of HCV infection. VEL combined with sofosbuvir (SOF) is Epclusa®, an STR with 98% cure-rates for genotype 1-6 HCV infected patients. Addition of the pan-genotypic HCV NS3/4A protease inhibitor voxilaprevir to SOF/VEL is the STR Vosevi®, which affords 97% cure-rates for genotype 1-6 HCV patients who have previously failed another treatment regimen.
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Antivirales/farmacología , Carbamatos/farmacología , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Carbamatos/síntesis química , Carbamatos/química , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Genotipo , Hepacivirus/genética , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Compuestos Macrocíclicos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Sofosbuvir/química , Relación Estructura-Actividad , Sulfonamidas/química , Comprimidos/química , Comprimidos/farmacología , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi® (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.
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Antivirales/farmacología , Carbamatos/química , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Inhibidores de Proteasas/farmacología , Sofosbuvir/química , Sulfonamidas/química , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Ácidos Aminoisobutíricos , Antivirales/síntesis química , Antivirales/química , Ciclopropanos , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Hepacivirus/genética , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compuestos Macrocíclicos/síntesis química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Prolina/análogos & derivados , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Quinoxalinas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
BACKGROUND: Voxilaprevir (VOX; GS-9857) is a pangenotypic HCV NS3/4A protease inhibitor (PI) with potent antiviral activity against HCV genotypes (GTs) 1-6 and improved coverage of GT1 NS3 resistance-associated substitutions (RAS) associated with other HCV PIs. In a 3-day Phase Ib monotherapy study in patients infected with HCV GT1a, 1b, 2, 3 and 4, VOX was well-tolerated and resulted in maximal mean viral load reduction >3 log10 IU/ml at the 100 mg dose across all genotypes evaluated. This report characterizes the HCV NS3 RAS in the study. METHODS: The NS3 gene was amplified and successfully deep sequenced using MiSeq for 66 patients at baseline and 61 patients post-baseline using 15% and 1% assay cutoffs. RESULTS: With a 15% assay cutoff, pretreatment HCV NS3 RAS were present in the HCV of 38% (9/24) of patients with GT1a and 5% (1/19) with GT3a; there were no pretreatment NS3 RAS present in patients with GT1b (n=6), GT2 (n=7) or GT4 (n=4). In patients with and without pretreatment NS3 RAS, ≥3.4 log10 mean maximal viral load reductions over 3 days of VOX administration were observed. The majority of patients did not have detectable treatment-emergent NS3 RAS and only 12% (7/53) and 26% (14/53) had emergent NS3 RAS using 15% and 1% cutoffs, respectively. No NS3 RAS were detected in patients with GT2 or GT4. A156T or A156V were the most prevalent emergent NS3 RAS in patients with GT1a or GT1b infection, but were not observed in patients with GT3 infection. CONCLUSIONS: The lack of selection of NS3 RAS in the majority of patients demonstrates a high resistance barrier for VOX. ClinicalTrails.gov identifier NCT02185794.
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Farmacorresistencia Viral , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Compuestos Macrocíclicos/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Sulfonamidas/uso terapéutico , Ácidos Aminoisobutíricos , Línea Celular , Ciclopropanos , Genotipo , Hepacivirus/enzimología , Hepacivirus/genética , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compuestos Macrocíclicos/farmacología , Prolina/análogos & derivados , Inhibidores de Proteasas/farmacología , Quinoxalinas , ARN Viral , Análisis de Secuencia de ARN , Sulfonamidas/farmacología , Factores de Tiempo , Resultado del Tratamiento , Carga Viral , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND AND AIMS: Pain is the hallmark of sickle cell anemia (SCA), presenting as recurrent acute events or chronic pain. Central sensitization, or enhanced excitability of the central nervous system, alters pain processing and contributes to the maintenance of chronic pain. Individuals with SCA demonstrate enhanced sensitivity to painful stimuli however central mechanisms of pain have not been fully explored. We hypothesized that adults with SCA would show evidence of central sensitization as observed in other diseases of chronic pain. METHODS: We conducted a prospective study of static and dynamic quantitative sensory tests in 30 adults with SCA and 30 matched controls. RESULTS: Static thermal testing using cold stimuli showed lower pain thresholds (p=0.04) and tolerance (p=0.04) in sickle cell subjects, but not for heat. However, SCA subjects reported higher pain ratings with random heat pulses (p<0.0001) and change in scores with temporal summation at the heat pain threshold (p=0.002). Similarly, with the use of pressure pain stimuli, sickle cell subjects reported higher pain ratings (p=0.04), but not higher pressure pain tolerance/thresholds or allodynia to light tactile stimuli. Temporal summation pain score changes using 2 pinprick probes (256 and 512mN) were significantly greater (p=0.004 and p=0.008) with sickle cell, and delayed recovery was associated with lower fetal hemoglobin (p=0.002 and 0.003). CONCLUSIONS: Exaggerated temporal summation responses provide evidence of central sensitization in SCA. IMPLICATIONS: The association with fetal hemoglobin suggests this known SCA modifier may have a therapeutic role in modulating central sensitization.
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Anemia de Células Falciformes/fisiopatología , Sensibilización del Sistema Nervioso Central , Dolor Crónico/fisiopatología , Hemoglobina Fetal , Umbral del Dolor , Adulto , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/complicaciones , Frío , Femenino , Calor , Humanos , Hiperalgesia , Masculino , Estudios Prospectivos , TactoAsunto(s)
Anemia de Células Falciformes/complicaciones , Antihipertensivos/uso terapéutico , Epoprostenol/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Adolescente , Adulto , Anemia de Células Falciformes/diagnóstico , Presión Sanguínea/efectos de los fármacos , Ecocardiografía , Epoprostenol/análogos & derivados , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Hipertensión Pulmonar/diagnóstico , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
Memory stem T cells (TSCMs) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. Hallmarks of autoimmune disease pathogenesis are abnormal CD4(+) and CD8(+) T cell activation. We investigated the TSCM subset in 55, 34, 43, and 5 patients with acquired aplastic anemia (AA), autoimmune uveitis, systemic lupus erythematosus, and sickle cell disease, respectively, as well as in 41 age-matched healthy controls. CD8(+) TSCM frequency was significantly increased in AA compared with healthy controls. An increased CD8(+) TSCM frequency at diagnosis was associated with responsiveness to immunosuppressive therapy, and an elevated CD8(+) TSCM population after immunosuppressive therapy correlated with treatment failure or relapse in AA patients. IFN-γ and IL-2 production was significantly increased in various CD8(+) and CD4(+) T cell subsets in AA patients, including CD8(+) and CD4(+) TSCMs. CD8(+) TSCM frequency was also increased in patients with autoimmune uveitis or sickle cell disease. A positive correlation between CD4(+) and CD8(+) TSCM frequencies was found in AA, autoimmune uveitis, and systemic lupus erythematosus. Evaluation of PD-1, CD160, and CD244 expression revealed that TSCMs were less exhausted compared with other types of memory T cells. Our results suggest that the CD8(+) TSCM subset is a novel biomarker and a potential therapeutic target for AA.
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Anemia Aplásica/inmunología , Anemia Aplásica/terapia , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Células Precursoras de Linfocitos T/inmunología , Adulto , Anciano , Anemia Aplásica/sangre , Anemia Aplásica/diagnóstico , Anemia de Células Falciformes/diagnóstico , Anemia de Células Falciformes/inmunología , Enfermedades Autoinmunes/inmunología , Biomarcadores/sangre , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/clasificación , Femenino , Humanos , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/inmunología , Activación de Linfocitos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Recurrencia , Subgrupos de Linfocitos T , Insuficiencia del Tratamiento , Uveítis/diagnóstico , Uveítis/inmunologíaRESUMEN
BACKGROUND: Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea. OBJECTIVES: We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010. METHODS: An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648. RESULTS: Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003-1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00-1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23-4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34-0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17-0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels. CONCLUSIONS: Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings.