RESUMEN
INTRODUCTION: Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. AIM: We evaluated the efficacy and safety of ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1-4 infection and an inherited bleeding disorder. METHODS: Ledipasvir-sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively. RESULTS: The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. CONCLUSION: Treatment with ledipasvir-sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.
Asunto(s)
Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Ribavirina/uso terapéutico , Sofosbuvir/uso terapéutico , Adulto , Anciano , Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Combinación de Medicamentos , Femenino , Fluorenos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.
Asunto(s)
Antivirales/administración & dosificación , Genotipo , Hepacivirus/clasificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Compuestos Macrocíclicos/administración & dosificación , Sulfonamidas/administración & dosificación , Adolescente , Adulto , Anciano , Ácidos Aminoisobutíricos , Antivirales/efectos adversos , Antivirales/farmacocinética , Antivirales/farmacología , Ciclopropanos , Método Doble Ciego , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Hepacivirus/aislamiento & purificación , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compuestos Macrocíclicos/efectos adversos , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/farmacología , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Prolina/análogos & derivados , Quinoxalinas , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Resultado del Tratamiento , Carga Viral , Adulto JovenRESUMEN
The interaction of lipoproteins with hepatitis C virus (HCV) has pathogenic and therapeutic implications. Our aim was to evaluate changes in the apolipoprotein profile of patients with chronic hepatitis C during and after successful cure with ledipasvir and sofosbuvir (LDV/SOF) with and without ribavirin (RBV). One hundred HCV genotype 1 patients who had achieved SVR-12 after treatment with 12 weeks of LDV/SOF ± RBV were selected from the ION-1 clinical trial. Frozen serum samples from baseline, end of treatment and week 4 of follow-up were used to assay apolipoproteins (apoAI, apoAII, apoB, apoCII, apoCIII, apoE) using the Multiplex platform to assess for changes in the apolipoprotein levels. At the end of treatment compared to baseline, a significant reduction in apoAII levels (-14.97 ± 63.44 µg/mL, P = 0.0067) and apoE levels (-4.38 ± 12.19 µg/mL, P < 0.001) was noted. These declines from baseline in apoAII (-16.59 ±66.15 µg/mL, P = 0.0075) and apoE (-2.66 ± 12.64 µg/mL, P = 0.015) persisted at 4 weeks of post-treatment follow-up. In multivariate analysis, treatment with LDV/SOF + RBV was independently associated with reduction in apoE (beta = 5.31 µg/mL, P = 0.002) (compared to RBV-free LDV/SOF) (P < 0.05). In contrast, apoCII levels overall increased from baseline to end of treatment (+2.74 ±11.76 µg/mL, P = 0.03) and persisted at 4 weeks of follow-up (+4.46 ± 12.81 µg/mL from baseline, P = 0.0005). Subgroup analysis revealed an increase in apoCII during treatment only in patients receiving LDV/SOF without RBV (+5.52 ± 11.92 µg/mL, P = 0.0007) but not in patients receiving LDV/SOF + RBV (P = 0.638). Treatment with LDV/SOF ± RBV is associated with a persistent reduction in the apolipoprotein AII and E after achieving cure. These data suggest that treatment with LDV/SOF ± RBV may be associated with alterations in serum apolipoproteins which could potentially impact viral eradication.
Asunto(s)
Antivirales/uso terapéutico , Apolipoproteínas/sangre , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Sofosbuvir/uso terapéutico , Quimioterapia Combinada , Femenino , Hepacivirus/efectos de los fármacos , Hepacivirus/metabolismo , Hepatitis C Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Ribavirina/uso terapéuticoRESUMEN
Deltamethrin-impregnated PVC dog collars were tested to assess if they were effective in protecting dogs from sand fly bites of Lutzomyia longipalpis and Lu. migonei. A protective effect against Old World species Phlebotomus perniciosus was demonstrated before. Four dogs wearing deltamethrin collars and three dogs wearing untreated collars (not impregnated with deltamethrin) were kept in separate kennels for over eight months in a village on the outskirts of Fortaleza in Ceará, Brazil. Periodically, a dog from each group was sedated, placed in a net cage for 2 h in which 150 female sand flies had been released 10-15 min before. Lu. longipalpis were used 4, 8, 12, 16, 22, 27, and 35 weeks after the attachment of the collars. Lu. migonei were used 3, 7, 11, 15, 22, 26, and 36 weeks after attachment. During 35 weeks, only 4.1% (81 of 2,022) Lu. longipalpis recovered from the nets with the deltamethrin collared dogs were engorged, an anti-feeding effect of 96%. Mortality initially was over 90% and at 35 weeks was 35% with half of the sand flies dying in the first 2 h. In contrast, 83% of the 2,094 Lu. longipalpis recovered from the nets containing the untreated collared dogs were engorged and the mortality ranged from zero to 18.8% on one occasion with 1.1% dying in the first 2 h. Similar findings were found with Lu. migonei: of 2,034 sand flies recovered over this period, only 70 were engorged, an anti-feeding effect of 96.5%, and mortality ranged from 91% initially to 46% at 36 weeks. In contrast, engorgement of controls ranged from 91 to71% and a mortality ranged from 3.5 to 29.8%. These studies show that deltamethrin impregnated collars can protect dogs against Brazilian sand flies for up to eight months. Thus, they should be useful in a program to control human and canine visceral leishmaniasis.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Mordeduras y Picaduras de Insectos/veterinaria , Insecticidas , Psychodidae , Piretrinas , Animales , Perros , Femenino , Mordeduras y Picaduras de Insectos/prevención & control , Leishmaniasis Visceral/prevención & control , Leishmaniasis Visceral/veterinaria , NitrilosRESUMEN
Interleukin-4 has been reported to critically modulate Borrelia burgdorferi infection and Lyme arthritis in experimental murine models. To determine the in vivo role of IL-4 in controlling Lyme carditis, we compared immunological responses and the severity of cardiac inflammation in wild-type BALB/c (IL-4 +/+) and IL-4 deficient BALB/c (IL-4 -/-) mice infected with B. burgdorferi by tick-bite. At day 15 and 30 post-infection IL-4 -/- mice produced significantly greater titers of spirochete-specific IgG2a than the wild-type IL-4 +/+ mice, which produced significantly more spirochete-specific IgG1. Following in vitro antigenic stimulation with B. burgdorferi antigen, splenocytes from infected IL-4 -/- and IL-4 +/+ mice displayed similar magnitudes of proliferative responses at day 15 and 30 post-infection. At day 30 antigen-stimulated splenocytes from infected IL-4 -/- mice, however, produced significantly more IFN-gamma than those derived from similarly infected IL-4 +/+ mice, suggesting that Th1-influenced responses predominated in IL-4 -/- mice. Moreover, inflamed hearts from IL-4 -/- mice displayed higher levels of IFN-gamma and TNF-alpha transcripts as compared to IL-4 +/+ mice. At both time points antigen-stimulated splenocytes from IL-4 +/+ and IL-4 -/- mice produced significant amounts of IL-10 but those from IL-4 +/+ mice produced either no or little IL-4. Histopathology demonstrated typical Lyme carditis in both IL-4 +/+ and IL-4 -/- mice at day 15 and day 30. Although Borrelia-infected IL-4 -/- mice developed a more severe carditis on day 30, the carditis resolved by day 50, as it did in IL4 +/+ mice. These results indicate that although IL-4 may help limit the severity of Lyme carditis, its absence does not preclude resolution of cardiac lesions.
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Interleucina-4/fisiología , Enfermedad de Lyme/inmunología , Miocarditis/inmunología , Células TH1/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Inmunoglobulina G/sangre , Inmunoglobulina G/clasificación , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Ratones , Ratones Endogámicos BALB CRESUMEN
NK cells have been shown to play a role in the modulation of B cell differentiation and Ab production. Using a novel murine model of NK cell deficiency, we analyzed the in vivo role of NK cells in the regulation of Ag-specific Ab production. After immunization with OVA or keyhole limpet hemocyanin in CFA, NK cell-deficient (NK-T+) mice developed an efficient Th1 response and produced significant levels of IFN-gamma but displayed markedly reduced or absent Ag-specific IgG2a production. There were no differences in the levels of Ag-specific IgG, IgG1, and IgG2b between NK-T+ and NK+T+ mice. Furthermore, NK cell-reconstituted, NK+T+ (tgepsilon26Y) mice produced significant amounts of Ag-specific IgG2a after immunization with OVA. These results indicate that NK cells are involved in the induction of Ag-specific IgG2a production in vivo. Moreover, they also demonstrate that the lack of Ag-specific IgG2a Ab production in NK-T+ mice is not associated with the impaired Th1 response and IFN-gamma production.
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Epítopos/inmunología , Inmunoglobulina G/biosíntesis , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Linfopenia/inmunología , Células TH1/inmunología , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Adyuvante de Freund/inmunología , Hemocianinas/administración & dosificación , Hemocianinas/inmunología , Inyecciones Subcutáneas , Interferón gamma/biosíntesis , Células Asesinas Naturales/patología , Linfopenia/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Moluscos , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Células TH1/citologíaRESUMEN
Recent studies have demonstrated that two IL-12 signaling pathways, a STAT 4 - dependent and STAT4 - independent, are involved in the development of a Th1-like response. To determine their roles in the development of protective immunity against Leishmania major, we monitored progression of cutaneous Leishmania major infection in STAT4-deficient mice (STAT4-/-) compared to similarly infected wild-type (STAT4+/+) mice. Although the onset of lesion growth was delayed in STAT4-/- mice during the early phase of infection, these mice eventually developed large, non-healing lesions, whereas STAT4+/+ mice resolved their lesions. As infection progressed, both STAT4+/+ and STAT4-/- mice infected with L. major displayed similar titers of Leishmania-specific IgG1 and IgE but later produced lower IgG2a. On days 20 and 40 post-infection, Leishmania antigen-stimulated lymphnode cells from STAT4-/- mice produced significantly lower amounts of IFN-gamma than those from STAT4+/+ mice as measured by enzyme-linked immunosorbent assay. There was no significant difference, however, in IL-4 and IL-12 production between the two groups. These results indicate that STAT4-mediated IL-12 signaling is critical for the development of protective Th1 response following L. major infection in genetically resistant mice. Additionally, they demonstrate that, although genetically resistant mice lacking STAT4 signaling pathway develop large, non-healing lesions, they do not default towards a Th2-like response.
Asunto(s)
Proteínas de Unión al ADN/inmunología , Interleucina-12/metabolismo , Leishmaniasis Cutánea/inmunología , Transactivadores/inmunología , Animales , Citocinas/biosíntesis , Proteínas de Unión al ADN/genética , Interferón gamma/biosíntesis , Leishmania major/inmunología , Leishmania major/aislamiento & purificación , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT4 , Transducción de Señal , Células TH1/inmunología , Células Th2/inmunología , Transactivadores/genéticaRESUMEN
NK cells are believed to play a critical role in the development of immunity against Leishmania major. We recently found that transplantation of wild-type bone marrow cells into neonatal tgepsilon 26 mice, which are deficient in T and NK cells, resulted in normal T cell development, but no or poor NK cell development. Using this novel model we analyzed the role of NK cells in the development of Th1 response and control of cutaneous L. major infection. Mice selectively lacking NK cells (NK-T+) developed an efficient Th1-like response, produced significant amounts of IL-12 and IFN-gamma, and controlled cutaneous L. major infection. Administration of neutralizing IL-12 Abs to NK-T+ mice during L. major infection resulted in exacerbation of the disease. These results demonstrate that NK cells are not critical for development of protective immunity against L. major. Furthermore, they indicate that IL-12 can induce development of Th1 response independent of NK cells in NK-T+ mice following L.major infection.
Asunto(s)
Células Asesinas Naturales/inmunología , Leishmania major/inmunología , Leishmaniasis Cutánea/genética , Leishmaniasis Cutánea/inmunología , Linfopenia/inmunología , Células TH1/inmunología , Animales , Anticuerpos Antiprotozoarios/biosíntesis , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citotoxicidad Inmunológica/genética , Sueros Inmunes/administración & dosificación , Inmunoglobulina G/biosíntesis , Inyecciones Intraperitoneales , Interleucina-12/inmunología , Interleucina-12/fisiología , Células Asesinas Naturales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Células TH1/metabolismoRESUMEN
The cutaneous growth of Leishmania mexicana was measured in STAT6-deficient mice (STAT6-/-) and compared with that in similarly infected wild-type (STAT6+/+) mice. Following s.c. inoculation with 5 x 10(6) amastigotes of L. mexicana into the shaven rump, STAT6+/+ mice developed large, nonhealing cutaneous lesions, while STAT6-/- mice failed to develop detectable lesions during most of the course of study. As infection progressed, STAT6+/+ mice infected with L. mexicana displayed significantly higher titers of Leishmania-specific IgG1 and IgE compared with STAT6-/- mice, which conversely produced significantly higher titers of Leishmania-specific IgG2a, indicating development of a Th1-like response in the latter group. At 12 wk postinfection, Leishmania Ag-stimulated lymph node cells from STAT6-/- mice produced significantly higher amounts of IL-12 and IFN-gamma than those from STAT6+/+ mice as measured by ELISA. However, there was no significant difference in IL-4 production between the two groups. Semiquantitative RT-PCR of transcript levels in intact draining lymph nodes and skin from inoculation sites confirmed a similar pattern of cytokines in vivo as that observed in stimulated lymph node cells in vitro. These results indicate that STAT6-mediated IL-4 signaling is critical for progression of L. mexicana infection in genetically susceptible mice and demonstrate that in the absence of STAT6, susceptible mice default toward a Th1-like response and control cutaneous L. mexicana infection.