RESUMEN
INTRODUCTION AND OBJECTIVE: The aim of the present study was to investigate the significance of serum HBsAg levels in treatment cessation of nucleoside analogues (NAs) in patients with chronic hepatitis B (CHB) infection. METHODS: In 158 CHB patients with long-term NAs treatment, 74 patients were in HBeAg negative and had a HBsAg level <1500IU/mL, 36 of whom were informed and consented to cease NAs. HBsAg, HBV DNA and liver function were examined in the 1st, 3rd, 6th, 9th and 12th month after treatment cessation. RESULTS: The sustained response rate was 88.89% (32/36) within one year after NAs cessation. Sub-group analysis was based on HBsAg levels of patients with NAs cessation, there was no relapse case in 11 patients whose HBsAg <50IU/mL, and the negative predictive value (NPV) was 100%. Seroconversion of HBsAg occurred in 3 patients. 2 patients from 21 cases whose HBsAg was between 50IU/mL and 1000IU/mL relapsed. 2 of 4 patients whose in HBsAg >1000IU/mL relapsed. HBsAg of patients with a sustained response decreased slowly. In contrast, HBsAg levels increased gradually in relapsed patients, and the increase of HBsAg was precedent to relapses of HBV DNA and ALT. Multivariate analysis suggested that only HBsAg level showed a close correlation with HBV DNA relapses. ROC curve analysis suggested that the increase of HBsAg level in the 3rd and 6th month after NAs cessation had a great predictive value for relapses. CONCLUSION: Monitoring of base line HBsAg level can predict outcomes of NAs cessation in HBeAg-negative chronic hepatitis B. HBsAg <50IU/mL has higher predictive values of better sustained responses in HBeAg-negative CHB patients.
Asunto(s)
Antivirales/uso terapéutico , Antígenos de Superficie de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Respuesta Virológica Sostenida , Adenina/análogos & derivados , Adenina/uso terapéutico , Anciano , Alanina Transaminasa/sangre , ADN Viral , Deprescripciones , Duración de la Terapia , Femenino , Guanina/análogos & derivados , Guanina/uso terapéutico , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/sangre , Humanos , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Nucleósidos , Organofosfonatos/uso terapéutico , Recurrencia , Estudios Retrospectivos , Telbivudina/uso terapéuticoRESUMEN
In this paper, we report the synthesis of a new series of α-aminophosphonates derivatives based in an efficient three-component reaction. All compounds prepared showed significant anti-inflammatory activity, being the compounds 1a, 1c, 1d, 1f, 2b and 2c the most promising ones, in terms of maximal efficacy (over 95%), potency (ED50 range between 0.7 and 10.1â¯mg/ear) and relative potency (range from 0.04 to 0.67). Compounds 1a, 1c, 1d and 1f significantly decrease the number of neutrophils (range from 46.7 to 63.0%) and monocytes (18.9-34.1%) in blood samples from the orbital sinus. Additionally, QSAR model revealed that the spherical molecular shape and the location of the HOMO on the phenyl ring improves the anti-inflammatory activity of the compounds. The values of R2, Q2, s and F statistical parameters and the QUIK, asymptotic Q2 and Overfitting rules validate the descriptive and predictive ability of the QSAR model. Altogether these results suggest that these new α-aminophosphonates are potential agents for the treatment of inflammation.
Asunto(s)
Antiinflamatorios/uso terapéutico , Etanolaminas/uso terapéutico , Inflamación/tratamiento farmacológico , Organofosfonatos/uso terapéutico , Relación Estructura-Actividad Cuantitativa , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Etanolaminas/síntesis química , Etanolaminas/química , Ratones , Estructura Molecular , Monocitos/metabolismo , Neutrófilos/metabolismo , Organofosfonatos/síntesis química , Organofosfonatos/químicaRESUMEN
The Brazilian public health system (SUS) has provided antiviral drugs for chronic hepatitis B treatment for over 10 years, but a system for monitoring for drug-related resistance mutations is not available. Determine the presence of HBV mutations associated with resistance to nucleos(t)ide analogs among 81 patients with chronic HBV infection in Salvador-BA-Brazil. HBV-DNA was PCR amplified with primers deduced from the rt domain at the HBV P gene, the sequence extended 1032 bp (from amino acid 1 to 344-rt domain). Those sequences were submitted to the HBV drug resistance database to retrieve each mutation according to the genotype. HBV genotype A1 (85.2%) was the most prevalent, followed by genotype A2 (4.9%), F (6.2%), and C1, D2, and D4 (1.2% each). Six patients (7%) exhibited resistance mutations to LAM, ETV, and TDF: two with patterns L180M + M204V and four with other different patterns: L80I + L180M + M204I; L80V + L180M + M204V; M204I; A194T. All of these mutations were present in patients with genotype A (four A1 and two A2). In addition, four mutations in gene S (three cases with the sI195M mutation and one with the W196L mutation), were detected, corresponding to a rate of 6% of vaccine escape mutations. Althougth the small sample size, an association was found between the occurrence of HBV resistance mutations and HBeAg positivity, co-infection with HIV and a history of treatment for HBV and/or HIV.
Asunto(s)
Farmacorresistencia Viral/genética , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Hepatitis B Crónica/virología , Adulto , Antivirales/uso terapéutico , Brasil/epidemiología , Coinfección/epidemiología , Coinfección/virología , ADN Viral/genética , Genotipo , Vacunas contra Hepatitis B , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/epidemiología , Humanos , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Mutación , Organofosfonatos/uso terapéuticoRESUMEN
Two hundred forty million people are chronically infected with hepatitis B virus (HBV) worldwide. The rise of globalization has facilitated the emergence of novel HBV recombinants and genotypes. We evaluated HBV genotypes and recombinants, mutations associated with resistance to antivirals (AVs), progression of hepatic illness, and inefficient hepatitis B vaccination responses in chronically infected individuals in the city of São Paulo, Brazil. Forty-five full-length and 24 partial-length sequences were obtained. The genotype distribution was as follows: A (66.7%), D (15.9%), F (11.6%) and C (4.3%). We describe a new recombinant (D2/D3), confirmed through next-generation sequencing (NGS) and reconstruction of the quasispecies sequences in silico. Primary resistance and major vaccine escape mutations were not found. We did, however, find mutations in the S region that might may be related to HBV antigenicity changes, as well as Pre-S deletions. The precore/core mutations A1762T + G1764A (40.9%) were found mostly in genotypes A and D, and G1896A (29.55%) was more frequent in genotype D than in genotype A. The genotypic distribution reflects the history of Brazilian immigration. This is the first description of recombination between genotypes D2 and D3 in Brazil. It is also the first confirmation through NGS and reconstruction of the quasispecies in silico. However, little is known about the response to treatment of recombinants. This demonstrates the need for molecular epidemiology studies involving the analysis of full-length HBV sequences.
Asunto(s)
Farmacorresistencia Viral/genética , Virus de la Hepatitis B/genética , Hepatitis B Crónica/epidemiología , Virus Reordenados/genética , Recombinación Genética , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Anciano , Antivirales/uso terapéutico , Brasil/epidemiología , Femenino , Genotipo , Virus de la Hepatitis B/clasificación , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/transmisión , Hepatitis B Crónica/virología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Epidemiología Molecular , Mutación , Organofosfonatos/uso terapéutico , Filogenia , Virus Reordenados/clasificación , Virus Reordenados/efectos de los fármacos , Virus Reordenados/aislamiento & purificación , Estudios RetrospectivosRESUMEN
Conventional interferon alfa and nucleos(t)ide analogues, such as lamivudine, are frequently used for chronic hepatitis B (CHB) treatment, but are associated with adverse effects and viral resistance. Here we performed a systematic review and meta-analysis evaluating all studies of pegylated interferon alfa (PEG-IFNα) treatment in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with CHB. We searched electronic databases--PubMed, EMBASE, Cochrane Library and LILACS--for randomized controlled trials evaluating PEG-IFNα therapy between 1999 and September 2014. Virological response was the primary outcome. We identified 14 studies involving 2829 patients. Our analysis revealed that PEG-IFNα + lamivudine combination therapy produced better virological and biochemical responses than PEG-IFNα monotherapy in HBeAg-positive and HBeAg-negative patients at the end of treatment. PEG-IFNα + adefovir dipivoxil achieved better seroconversion rate than PEG-IFNα in HBeAg-positive patients at the end of treatment. The present findings demonstrated a beneficial response rate following PEG-IFNα combination therapy with nucelos(t)ides among HBeAg-positive and HBeAg-negative patients with CHB. Further trials are needed to investigate simultaneous and sequential therapy strategies.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Adenina/análogos & derivados , Adenina/uso terapéutico , Quimioterapia Combinada/métodos , Antígenos e de la Hepatitis B/sangre , Humanos , Lamivudine/uso terapéutico , Organofosfonatos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Carga ViralRESUMEN
INTRODUCTION: Among the available nucleos(t)ide analogues adefovir dipivoxil (ADV) is relatively cheap and widely used in rural area in China. However, there are insufficient data on recommendation for patients with suboptimal response to ADV after 48 weeks of treatment in order to reduce the resistance rate in the long term. The aim of this study was to compare the efficacy and safety of LAM add-on combination therapy versus ETV monotherapy for patients with suboptimal response to ADV. MATERIAL AND METHODS: 136 patients with suboptimal response to ADV were randomly assigned to the add-on LAM with ADV combination therapy (68 patients) group and the ETV monotherapy (68 patients) group. Patients in the add-on group were prescribed 100 mg LAM and 10 mg ADV per day, while the monotherapy group received 0.5 mg ETV per day for 48 weeks. Tests for liver and kidney function, HBV serum markers, HBV DNA load, were performed every 3 months. RESULTS: The mean patient age in LAM add-on group and ETV monotherapy was 38.59 ± 7.65 and 37.56 ± 8.67 years respectively. The HBV DNA undetectable rate in the LAM add-on group and the ETV group were not significant difference at week 4, 12 and 24 (P > 0.05). However, the HBV undetectable rate in the ETV group was higher than that in the LAM add-on group at week 36 and 48 (P = 0.043 for week 36 and P = 0.038 for week 48). There was no significant difference both for HBeAg loss and HBeAg seroconversion between two groups (P > 0.05) at 48 weeks. Meanwhile, our study also demonstrated that the mean eGFR levels in LAM add-on group was decreased from 99.6 ± 8.71 at baseline to 86.4 ± 9.83 at the end of 48 weeks, which was significantly higher than that in the ETV monotherapy group (P < 0.05). 8.8% of patients in LAM add-on group experienced eGFR reduction by 20-30% from baseline at 48 weeks. No patients developed hyposphosphatemia in our study. CONCLUSION: Our study clearly showed that switch to ETV monotherapy was the more effective and more safe than that of LAM add-on combination therapy for patients with suboptimal response to ADV.
Asunto(s)
Adenina/análogos & derivados , Antivirales/uso terapéutico , Sustitución de Medicamentos , Guanina/análogos & derivados , Hepatitis B Crónica/tratamiento farmacológico , Lamivudine/uso terapéutico , Organofosfonatos/uso terapéutico , Adenina/efectos adversos , Adenina/uso terapéutico , Adulto , Antivirales/efectos adversos , Biomarcadores/sangre , China , Quimioterapia Combinada , Femenino , Guanina/efectos adversos , Guanina/uso terapéutico , Hepatitis B Crónica/sangre , Hepatitis B Crónica/diagnóstico , Humanos , Lamivudine/efectos adversos , Masculino , Persona de Mediana Edad , Organofosfonatos/efectos adversos , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
Proximal renal tubular dysfunction (PRTD) of varying severity has been associated with antiretroviral toxicity, especially related to the use of tenofovir (TDF). The aim of this study was to investigate whether HIV-infected patients who use a tenofovir-based regimen are at increased risk of tubular dysfunction. We conducted an observational, comparative, longitudinal, prospective study. Estimated glomerular filtration rate (eGFR) and markers of tubular damage to assess tubular dysfunction (fractional excretion of phosphate and uric acid, glycosuria, and proteinuria) were measured at baseline and at weeks 12 and 24. Of 111 participants, PRTD was found in 6.3% at week 12 and 9% at week 24, with no statistically significant difference between those on an abacavir (ABC)-containing regimen or a TDF-containing regimen. We also found an increase in triglycerides associated with the ABC-containing regimen compared with the TDF group. The use of an ABC- or TDF-containing regimen was independently associated with tubular dysfunction, but we found no significant differences between these groups, except when TDF was combined with a protease inhibitor. A better and more complete assessment of renal function is needed, because the presence of tubular dysfunction and proteinuria without impairment of eGFR may affect the renal safety of HIV-infected patients.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Túbulos Renales Proximales/efectos de los fármacos , Organofosfonatos/efectos adversos , Adenina/efectos adversos , Adenina/uso terapéutico , Adolescente , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/efectos adversos , Didesoxinucleósidos , Quimioterapia Combinada , Femenino , Tasa de Filtración Glomerular , Infecciones por VIH/complicaciones , Infecciones por VIH/fisiopatología , Humanos , Túbulos Renales Proximales/fisiopatología , Estudios Longitudinales , Masculino , México , Persona de Mediana Edad , Organofosfonatos/uso terapéutico , Estudios Prospectivos , Inhibidores de Proteasas/uso terapéutico , Proteinuria/inducido químicamente , Proteinuria/fisiopatología , TenofovirRESUMEN
BACKGROUND/AIMS: The most common HBV genotypes in HIV-coinfected patients in Mexico are H and G; the response to treatment for these genotypes is unknown. The aim of the study was to examine the effectiveness of intensification with pegylated interferon (PEG-IFN) alfa-2a or alfa-2b in HBV/HIV-coinfected patients treated with a tenofovir/emtricitabine (TDF/FTC) backbone in an HIV clinic in Mexico City. METHODOLOGY: We performed a single-arm open-label trial involving HBV/HIV-coinfected patients. Patients with chronic hepatitis B who were HBeAg positive were treated with TDF/FTC-containing regimen. Treatment was intensified by addition of PEG-IFN alfa-2b or alfa-2a for 24 weeks. The primary endpoint of effectiveness, assessed after 24 weeks, was suppression of HBV DNA to <60 IU/mL. RESULTS: We enrolled 29 patients; 27 (93%) were men. HBV genotypes were F in 2 (6.9%), A in 2 (6.9%), G in 10 (34.5%), and H in 15 (51.7%). The primary endpoint was present in 17 (58%) patients (95% CI 29.7%70.8%). CONCLUSIONS: Intensification with PEG-IFN alfa-2a or alfa-2b is effective and well tolerated in patients with chronic hepatitis B who are HBeAg positive, have genotype H or G, and are coinfected with HIV while they are being treated with TDF/FTC-containing regimen.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Coinfección , Desoxicitidina/análogos & derivados , Infecciones por VIH/tratamiento farmacológico , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Organofosfonatos/uso terapéutico , Polietilenglicoles/uso terapéutico , Adenina/uso terapéutico , Adulto , Biomarcadores/sangre , ADN Viral/sangre , Desoxicitidina/uso terapéutico , Quimioterapia Combinada , Emtricitabina , Femenino , Genotipo , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/diagnóstico , Humanos , Interferón alfa-2 , Masculino , México , Proteínas Recombinantes/uso terapéutico , Tenofovir , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
UNLABELLED: BACKGROUND AND RATIONALE OF THE STUDY: Effect of Long-term nucleoside/nucleotide (NUC) on hepatocellular carcinoma (HCC) incidence in a population of HBeAg-negative genotype D patients has not been adequately studied in real-life cohorts. Our aim was to evaluate the impact of liver fibrosis and other variables on HCC incidence in this population of patients. Of 745 patients with chronic hepatitis B (CHB), 306 HBeAg-negative genotype D were selected and included in this study. All patients received treatment with NUC for at least 18 months. Patients with CHB or compensated cirrhosis were included. Patients with HCC diagnosed before or during the first 18 months of NUC therapy were excluded. RESULTS: HCC was diagnosed in 2 CHB patients (1.0%) and 23 cirrhosis patients (20%) (OR = 24.41, 95% CI 5.40 < OR < 153.2; p < 0.0001). Multivariate analysis revealed that HCC risk was independently associated with age ≥ 60 years (OR = 6.45, 95% CI 1.22 to 34.0; p = 0.02) and liver cirrhosis (OR = 12.1, 95% CI 1.39 to 106.2; p = 0.02), but not with virological response (VR), and previous resistance to NUC, or rescue therapy. Multivariate analysis in cirrhosis patients revealed that only age ≥ 60 years was an independent risk factor associated with HCC (p = 0.003). CONCLUSIONS: Liver cirrhosis and age ≥ 60 years are the stronger risk factors for HCC in genotype D HBeA-gnegative patients. Previous resistance to NUC in patients that achieved a VR after rescue therapy was not a predictive factor regarding HCC. VR does not appear to significantly reduce the overall incidence of HCC when a patient has already progressed to liver cirrhosis.
Asunto(s)
Antivirales/uso terapéutico , Carcinoma Hepatocelular/etiología , Hepatitis B Crónica/tratamiento farmacológico , Neoplasias Hepáticas/etiología , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Anciano , Estudios de Cohortes , ADN Viral/genética , Femenino , Guanina/análogos & derivados , Guanina/uso terapéutico , Antígenos e de la Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/inmunología , Humanos , Lamivudine/uso terapéutico , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Organofosfonatos/uso terapéutico , Estudios Retrospectivos , Telbivudina , Tenofovir , Timidina/análogos & derivados , Timidina/uso terapéutico , Carga ViralRESUMEN
Results from phase III clinical trials clearly demonstrate the efficacy and safety of entecavir and tenofovir in the controlled environment of randomized clinical studies. There are several studies with both drugs performed in clinical practice (also called "real life studies"). Despite the pros and cons, studies performed in real life conditions represent everyday practice and add important information about long term treatment effectiveness and safety in this clinical setting. This review shows that patients treated with first line nucleos(t)ide analogs at referral centres, with good clinical follow-up and adherence to international guidelines, can achieve high treatment response rates with a very low rate of adverse events.
Asunto(s)
Adenina/análogos & derivados , Antivirales/uso terapéutico , Guanina/análogos & derivados , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , Organofosfonatos/uso terapéutico , Adenina/efectos adversos , Adenina/uso terapéutico , Antivirales/efectos adversos , Guanina/efectos adversos , Guanina/uso terapéutico , Virus de la Hepatitis B/crecimiento & desarrollo , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/virología , Humanos , Organofosfonatos/efectos adversos , Tenofovir , Resultado del TratamientoRESUMEN
BACKGROUND: Concurrent treatment of HIV and tuberculosis is complicated by drug interactions. We explored the safety and efficacy of raltegravir as an alternative to efavirenz for patients co-infected with HIV and tuberculosis. METHODS: We did a multicentre, phase 2, non-comparative, open-label, randomised trial at eight sites in Brazil and France. Using a computer-generated randomisation sequence, we randomly allocated antiretroviral-naive adult patients with HIV-1 and tuberculosis (aged ≥18 years with a plasma HIV RNA concentration of >1000 copies per mL) to receive raltegravir 400 mg twice a day, raltegravir 800 mg twice daily, or efavirenz 600 mg once daily plus tenofovir and lamivudine (1:1:1; stratified by country). Patients began study treatment after the start of tuberculosis treatment. The primary endpoint was virological suppression at 24 weeks (HIV RNA <50 copies per mL) in all patients who received at least one dose of study drug (modified intention-to-treat analysis). We recorded death, study drug discontinuation, and loss to follow-up as failures to achieve the primary endpoint. We assessed safety in all patients who received study drugs. This study is registered in ClinicalTrials.gov, number NCT00822315. FINDINGS: Between July 3, 2009, and June 6, 2011, we enrolled and randomly assigned treatment to 155 individuals; 153 (51 in each group) received at least one dose of the study drug and were included in the primary analysis. 133 patients (87%) completed follow-up at week 48. At week 24, virological suppression was achieved in 39 patients (76%, 95% CI 65-88) in the raltegravir 400 mg group, 40 patients (78%, 67-90) in the raltegravir 800 mg group, and 32 patients (63%, 49-76) in the efavirenz group. The adverse-event profile was much the same across the three groups. Three (6%) patients allocated to efavirenz and three (6%) patients allocated to raltegravir 800 mg twice daily discontinued the study drugs due to adverse events. Seven patients died during the study (one in the raltegravir 400 mg group, four in the raltegravir 800 mg group, and two in the efavirenz group): none of the deaths was deemed related to study treatment. INTERPRETATION: Raltegravir 400 mg twice daily might be an alternative to efavirenz for the treatment of patients co-infected with HIV and tuberculosis. FUNDING: French National Agency for Research on AIDS and Viral Hepatitis (ANRS), Brazilian National STD/AIDS Program-Ministry of Health.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Pirrolidinonas/administración & dosificación , Tuberculosis/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Alquinos , Fármacos Anti-VIH/efectos adversos , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , Benzoxazinas/uso terapéutico , Brasil , Coinfección , Ciclopropanos , Quimioterapia Combinada , Femenino , Francia , Infecciones por VIH/complicaciones , Humanos , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Organofosfonatos/uso terapéutico , Pirrolidinonas/efectos adversos , ARN Viral/sangre , Raltegravir Potásico , Tenofovir , Resultado del Tratamiento , Tuberculosis/complicaciones , Carga ViralRESUMEN
This study assessed the clinical efficacy of lamivudine and adefovir dipivoxil combined with autologous bone marrow stem cell transplantation as treatment for patients with hepatitis B and decompensated liver cirrhosis. In total, 77 patients with hepatitis B and decompensated liver cirrhosis were randomly divided into two groups. Under general symptomatic and supportive treatment, the patients in group A (37 cases) were treated with lamivudine and adefovir dipivoxil, whereas those in group B (40 cases) were treated with autologous bone marrow stem cell transplantation in combination with lamivudine and adefovir dipivoxil. After 4 weeks of treatment, the liver function indicators and clinical signs and symptoms of the patients in group B improved more significantly than those of patients in group A. Lamivudine and adefovir dipivoxil in combination with autologous bone marrow stem cell transplantation effectively prevented hepatitis B virus infection and bone marrow stem cell damage. This combination treatment facilitates the differentiation of bone marrow stem cells into normal liver cells to restore liver structure and improve liver function, thereby improving the quality of life of patients.
Asunto(s)
Adenina/análogos & derivados , Virus de la Hepatitis B/efectos de los fármacos , Lamivudine/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/virología , Organofosfonatos/uso terapéutico , Trasplante de Células Madre , Adenina/efectos adversos , Adenina/farmacología , Adenina/uso terapéutico , Colinesterasas/metabolismo , Terapia Combinada , Femenino , Humanos , Lamivudine/efectos adversos , Lamivudine/farmacología , Cirrosis Hepática/fisiopatología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Organofosfonatos/efectos adversos , Organofosfonatos/farmacología , Tiempo de Protrombina , Trasplante de Células Madre/efectos adversos , alfa-Fetoproteínas/metabolismoRESUMEN
OBJECTIVES: To describe the clinical manifestations and short-term outcomes of adenoviral infections in neonates and review all published cases to better determine impact and treatment outcomes. STUDY DESIGN: Retrospective cohort study of all neonates hospitalized at Children's Medical Center (CMC) and Parkland Memorial Hospital (PMH), Dallas, TX with laboratory-confirmed adenoviral infection from January 1,1995-December 31, 2012. Neonates were identified by review of the CMC Virology Laboratory's prospective database of all positive adenovirus tests performed in the inpatient and ambulatory settings, and at PMH, of a prospective neonatal database that included all neonatal intensive care unit admissions. Patients also were identified by discharge International Classification of Disease, 9th edition codes for adenoviral infection. The medical records were reviewed, and a review of the English literature was performed. RESULTS: During 17 years, 26 neonates had adenoviral infection (25, CMC; 1, PMH). The principle reasons for hospitalization were respiratory signs (88%) and temperature instability (65%). Five (19%) had disseminated disease and 4 (80%) of these infants died. Ribavirin or cidofovir treatment, as well as immune globulin intravenous, did not improve outcomes except in 1 neonate. Literature review (n = 72) combined with our data found that disseminated infection was associated with death (68% vs 21% with localized infection, P < .001). In addition, neonates <14 days of age were more likely to have disseminated disease (44% vs 12%, P = .004) and death (48% vs 8%; P < .001). CONCLUSION: Adenoviral infection in hospitalized neonates was associated with severe morbidity and mortality, especially when infection was disseminated and involved the respiratory tract. Development of new therapeutic strategies is needed.
Asunto(s)
Infecciones por Adenoviridae/epidemiología , Adenoviridae/genética , Infecciones por Adenoviridae/tratamiento farmacológico , Factores de Edad , Antivirales/uso terapéutico , Temperatura Corporal , Cidofovir , Estudios de Cohortes , Tos/virología , Citosina/análogos & derivados , Citosina/uso terapéutico , Diarrea/virología , Fatiga/virología , Femenino , Hemorragia Gastrointestinal/virología , Hepatomegalia/virología , Humanos , Hipotensión/virología , Hipoxia/virología , Inmunoglobulinas Intravenosas/uso terapéutico , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Genio Irritable , Masculino , Hipotonía Muscular/virología , Organofosfonatos/uso terapéutico , Pancitopenia/virología , Reacción en Cadena de la Polimerasa , Ruidos Respiratorios , Estudios Retrospectivos , Ribavirina/uso terapéutico , Esplenomegalia/virología , Taquipnea/virología , Vómitos/virologíaRESUMEN
OBJECTIVE: To evaluate the cost-effectiveness of different drug therapies for chronic hepatitis B in adult patients. METHODS: Using a Markov model, a hypothetical cohort of 40 years for HBeAg-positive or HBeAg-negative patients was constructed. Adefovir, entecavir, tenofovir and lamivudine (with rescue therapy in cases of viral resistance) were compared for treating adult patients with chronic hepatitis B undergoing treatment for the first time, with high levels of alanine aminotransferase, no evidence of cirrhosis and without HIV co-infection. Values for cost and effect were obtained from the literature, and expressed in effect on life years (LY). A discount rate of 5% was applied. Univariate sensitivity analysis was conducted to assess model uncertainties. RESULTS: Initial treatment with entecavir or tenofovir showed better clinical outcomes. The lowest cost-effectiveness ratio was for entecavir in HBeAg-positive patients (R$ 4,010.84/LY) and lamivudine for HBeAg-negative patients (R$ 6,205.08/LY). For HBeAg-negative patients, the incremental cost-effectiveness ratio of entecavir (R$ 14,101.05/LY) is below the threshold recommended by the World Health Organization. Sensitivity analysis showed that variation in the cost of drugs may make tenofovir a cost-effective alternative for both HBeAg-positive and HBeAg-negative patients. CONCLUSIONS: Entecavir is the recommended alternative to start treating patients with chronic hepatitis B in Brazil. However, if there is a reduction in the cost of tenofovir, it can become a cost-effective alternative.
Asunto(s)
Antivirales/economía , Hepatitis B Crónica/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/economía , Adenina/uso terapéutico , Adulto , Análisis de Varianza , Antivirales/clasificación , Antivirales/uso terapéutico , Brasil , Análisis Costo-Beneficio , Progresión de la Enfermedad , Guanina/análogos & derivados , Guanina/economía , Guanina/uso terapéutico , Virus de la Hepatitis B , Humanos , Lamivudine/economía , Lamivudine/uso terapéutico , Cadenas de Markov , Organofosfonatos/economía , Organofosfonatos/uso terapéutico , Tenofovir , Resultado del TratamientoRESUMEN
The aim of this study was to conduct a cost-utility study of adefovir, entecavir, interferon alpha, pegylated interferon alpha, lamivudine and tenofovir for chronic hepatitis B in the context of Brazilian Public Health Care System. A systematic review was carried out for efficacy and safety. Another review was performed to collect utility data and transition probabilities between health states. A Markov model was developed in a time horizon of 40 years with annual cycles for three groups of: HBeAg positive, HBeAg negative, and all patients. These strategies were compared to a fourth group that received no treatment. Discount rates of 5% were applied and sensitivity analyses were performed. Tenofovir offered the best cost-utility ratio for the three evaluated models: U$397, U$385 and U$384 (per QALY, respectively, for HBeAg positive, negative, and all patients). All other strategies were completely dominated because they showed higher costs and lower effectiveness than tenofovir. The sequence of cost-utility in the three models was: tenofovir, entecavir, lamivudine, adefovir, telbivudine, pegylated interferon alpha, and interferon alpha. In the sensitivity analysis, adefovir showed lower cost-utility than telbivudine in some situations. The study has some limitations, primarily related to the creation of scenarios and modeling. In this study, tenofovir presented the best cost-utility ratio. The results obtained in this study will be valuable in decision-making and in the review of the clinical protocol, mainly involving the allocation of available resources for health care.
Asunto(s)
Femenino , Humanos , Masculino , Antivirales/economía , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/economía , Adenina/uso terapéutico , Antivirales/uso terapéutico , Brasil , Análisis Costo-Beneficio , Quimioterapia Combinada/economía , Guanina/análogos & derivados , Guanina/economía , Guanina/uso terapéutico , Interferón-alfa/economía , Interferón-alfa/uso terapéutico , Lamivudine/economía , Lamivudine/uso terapéutico , Cadenas de Markov , Organofosfonatos/economía , Organofosfonatos/uso terapéutico , Polietilenglicoles/economía , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/economía , Proteínas Recombinantes/uso terapéuticoRESUMEN
OBJETIVO Avaliar o custo-efetividade de diferentes tratamentos medicamentosos para hepatite B crônica entre pacientes adultos. MÉTODOS Utilizando modelo de Markov, construiu-se coorte hipotética de 40 anos para pacientes HBeAg-positivo ou HBeAg-negativo. Foram comparados os usos de adefovir, entecavir, tenofovir e lamivudina (com terapia de resgate em caso de resistência viral) para tratamento de pacientes adultos com hepatite B crônica, virgens de tratamento, com elevados níveis de alanina aminotransferase, sem evidência de cirrose e sem coinfecção por HIV. Valores para custo e efeito foram obtidos da literatura. A medida do efeito foi expressa em anos de vida ganhos (AVG). Taxa de desconto de 5% foi aplicada. Análise de sensibilidade univariada foi conduzida para avaliar incertezas do modelo. RESULTADOS O tratamento inicial com entecavir ou tenofovir apresentou melhores resultados clínicos. As menores razões custo-efetividade foram de entecavir para pacientes HBeAg-positivo (R$ 4.010,84/AVG) e lamivudina para pacientes HBeAg-negativo (R$ 6.205,08/AVG). Para pacientes HBeAg-negativo, a razão custo-efetividade incremental de entecavir (R$ 14.101,05/AVG) está abaixo do limiar recomendado pela Organização Mundial da Saúde. Análise de sensibilidade mostrou que variação nos custos dos medicamentos pode tornar tenofovir alternativa custo-efetiva tanto para pacientes HBeAg-positivo quanto para HBeAg-negativo. CONCLUSÕES Entecavir é alternativa recomendada para iniciar o tratamento de pacientes com hepatite B crônica no Brasil. Contudo, se houver redução no custo de tenofovir, esta pode se tornar alternativa mais custo-efetiva. .
OBJETIVO Evaluar el costo-efectividad de diferentes tratamientos medicamentosos para hepatitis B crónica entre pacientes adultos. MÉTODOS Utilizando el modelo de Markov, se construyó cohorte hipotética de 40 años para pacientes HBeAg-positivo o HBeAg-negativo. Se compararon los usos de adefovir, entecavir, tenofovir y lamivudina (con terapia de rescate en caso de resistencia viral) para tratamiento de pacientes adultos con hepatitis B crónica, vírgenes de tratamiento, con elevados niveles de alanina aminotransferasa, sin evidencia de cirrosis y sin coinfección por VIH. Valores para costo y efecto fueron obtenidos de la literatura y efecto en años de vida ganados (AVG). Tasa de descuento de 5% fue aplicada. Análisis de sensibilidad univariado fue conducido para evaluar incertidumbres del modelo. RESULTADOS El tratamiento inicial con entecavir o tenofovir presentó mejores resultados clínicos. Los menores cocientes costo-efectividad fueron de entecavir para pacientes HBeAg-positivo (R.010,84/AVG) y lamivudina para pacientes HBeAg-negativo (R.205,08/AVG).Para pacientes HBeAg-negativo, el cociente costo-efectividad incrementado de entecavir (R.101,05/AVG) está por debajo del límite recomendado por la Organización Mundial de la Salud. El análisis de sensibilidad mostró que la variación en los costos de los medicamentos puede tornar tenofovir una alternativa costo-efectiva tanto para pacientes HBeAg-positivo como para los HBeAg-negativo. CONCLUSIONES Entecavir es una alternativa recomendada para iniciar el tratamiento de pacientes con hepatitis B crónica en Brasil. Sin embargo, al haber reducción en el costo de tenofovir, éste puede convertirse en una alternativa más costo-efectiva. .
OBJECTIVE To evaluate the cost-effectiveness of different drug therapies for chronic hepatitis B in adult patients. METHODS Using a Markov model, a hypothetical cohort of 40 years for HBeAg-positive or HBeAg-negative patients was constructed. Adefovir, entecavir, tenofovir and lamivudine (with rescue therapy in cases of viral resistance) were compared for treating adult patients with chronic hepatitis B undergoing treatment for the first time, with high levels of alanine aminotransferase, no evidence of cirrhosis and without HIV co-infection. Values for cost and effect were obtained from the literature, and expressed in effect on life years (LY). A discount rate of 5% was applied. Univariate sensitivity analysis was conducted to assess model uncertainties. RESULTS Initial treatment with entecavir or tenofovir showed better clinical outcomes. The lowest cost-effectiveness ratio was for entecavir in HBeAg-positive patients (R$ 4,010.84/LY) and lamivudine for HBeAg-negative patients (R$ 6,205.08/LY). For HBeAg-negative patients, the incremental cost-effectiveness ratio of entecavir (R$ 14,101.05/LY) is below the threshold recommended by the World Health Organization. Sensitivity analysis showed that variation in the cost of drugs may make tenofovir a cost-effective alternative for both HBeAg-positive and HBeAg-negative patients. CONCLUSIONS Entecavir is the recommended alternative to start treating patients with chronic hepatitis B in Brazil. However, if there is a reduction in the cost of tenofovir, it can become a cost-effective alternative. .
Asunto(s)
Adulto , Humanos , Antivirales/economía , Hepatitis B Crónica/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/economía , Adenina/uso terapéutico , Análisis de Varianza , Antivirales/clasificación , Antivirales/uso terapéutico , Brasil , Análisis Costo-Beneficio , Progresión de la Enfermedad , Guanina/análogos & derivados , Guanina/economía , Guanina/uso terapéutico , Virus de la Hepatitis B , Lamivudine/economía , Lamivudine/uso terapéutico , Cadenas de Markov , Organofosfonatos/economía , Organofosfonatos/uso terapéutico , Resultado del TratamientoAsunto(s)
Antirretrovirales/uso terapéutico , Sarcoma de Kaposi/tratamiento farmacológico , Sarcoma de Kaposi/patología , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/patología , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Alquinos , Benzoxazinas/uso terapéutico , Ciclopropanos , Quimioterapia Combinada , Humanos , Lamivudine/uso terapéutico , Masculino , Organofosfonatos/uso terapéutico , TenofovirRESUMEN
The aim of this study was to conduct a cost-utility study of adefovir, entecavir, interferon alpha, pegylated interferon alpha, lamivudine and tenofovir for chronic hepatitis B in the context of Brazilian Public Health Care System. A systematic review was carried out for efficacy and safety. Another review was performed to collect utility data and transition probabilities between health states. A Markov model was developed in a time horizon of 40 years with annual cycles for three groups of: HBeAg positive, HBeAg negative, and all patients. These strategies were compared to a fourth group that received no treatment. Discount rates of 5% were applied and sensitivity analyses were performed. Tenofovir offered the best cost-utility ratio for the three evaluated models: U$397, U$385 and U$384 (per QALY, respectively, for HBeAg positive, negative, and all patients). All other strategies were completely dominated because they showed higher costs and lower effectiveness than tenofovir. The sequence of cost-utility in the three models was: tenofovir, entecavir, lamivudine, adefovir, telbivudine, pegylated interferon alpha, and interferon alpha. In the sensitivity analysis, adefovir showed lower cost-utility than telbivudine in some situations. The study has some limitations, primarily related to the creation of scenarios and modeling. In this study, tenofovir presented the best cost-utility ratio. The results obtained in this study will be valuable in decision-making and in the review of the clinical protocol, mainly involving the allocation of available resources for health care.
Asunto(s)
Antivirales/economía , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/tratamiento farmacológico , Adenina/análogos & derivados , Adenina/economía , Adenina/uso terapéutico , Antivirales/uso terapéutico , Brasil , Análisis Costo-Beneficio , Quimioterapia Combinada/economía , Femenino , Guanina/análogos & derivados , Guanina/economía , Guanina/uso terapéutico , Humanos , Interferón-alfa/economía , Interferón-alfa/uso terapéutico , Lamivudine/economía , Lamivudine/uso terapéutico , Masculino , Cadenas de Markov , Organofosfonatos/economía , Organofosfonatos/uso terapéutico , Polietilenglicoles/economía , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/economía , Proteínas Recombinantes/uso terapéutico , TenofovirRESUMEN
This study aimed to evaluate the efficacy and safety of entecavir and/or tenofovir in compensated (CC) or decompensated (DC) hepatitis B cirrhotic patients in real-life clinical practice. Of the 48 patients, included between April 2007 and March 2010, 12 were DC. The mean age was 55 ± 12.2 years, 85.4% were Caucasians and 8 patients were HBeAg positive. Mean viral load was 5.2 ± 1.9 log(10) UI/mL. HBV-DNA undetectability at 3, 6, 12 and 24 months were 53.3%, 78.3%, 83.7% and 97.1%, respectively, similar in CC and DC. At 6 and 12 months, ≥ 80% of CC achieved ALT normalization, while only 42.9% and 71.4% in DC. After a median follow-up of 27.1 (0.7-45.3) months, 43 patients were Child Pugh Turcotte (CPT) class A (n = 39 at entry). In DC, progressive improvement in the MELD scores was observed: 12.73 (SD 4.5), 10.4 (SD 3.6) and 8.2 (SD 2.6), at baseline, 12 and 24 months, respectively. During follow-up, 7 patients died, 4 received liver transplantation and 5 developed hepatocellular carcinoma. In three out of four DC who died due to hepatic causes, these events occurred between the first 0.7 and 6.7 months, and all were CPT class C. Cumulative survival in CC vs. DC at 12 and 24 months were 94.4% vs. 66.7%, and 88.2% vs. 57.1%, respectively (log rank p = 0.03). No severe adverse events associated with entecavir or tenofovir were reported. In conclusion, in compensated and decompensated cirrhotic patients, entecavir and tenofovir were effective and well tolerated.
Asunto(s)
Adenina/análogos & derivados , Antivirales/uso terapéutico , Guanina/análogos & derivados , Hepatitis B Crónica/tratamiento farmacológico , Cirrosis Hepática/virología , Organofosfonatos/uso terapéutico , Adenina/efectos adversos , Adenina/uso terapéutico , Adulto , Anciano , Antivirales/efectos adversos , Biomarcadores/sangre , Carcinoma Hepatocelular/virología , Distribución de Chi-Cuadrado , ADN Viral/sangre , Progresión de la Enfermedad , Quimioterapia Combinada , Femenino , Guanina/efectos adversos , Guanina/uso terapéutico , Antígenos e de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/mortalidad , Humanos , Estimación de Kaplan-Meier , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/mortalidad , Cirrosis Hepática/cirugía , Neoplasias Hepáticas/virología , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Organofosfonatos/efectos adversos , Estudios Retrospectivos , Tenofovir , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: Reduced atazanavir exposure has been demonstrated during pregnancy with standard atazanavir/ritonavir dosing. We studied an increased dose during the third trimester of pregnancy. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials Group 1026s is a prospective, nonblinded, pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including 2 cohorts (with or without tenofovir) receiving atazanavir/ritonavir 300/100 mg once daily during the second trimester, 400/100 mg during the third trimester, and 300/100 mg postpartum (PP). Intensive steady-state 24-hour pharmacokinetic profiles were performed. Atazanavir concentrations were measured by high-performance liquid chromatography. Pharmacokinetic targets were the 10th percentile atazanavir area under the concentration versus time curve (AUC) (29.4 µg·hr·mL·) in nonpregnant adults on standard dose and 0.15 µg/mL, minimum trough concentration. RESULTS: Atazanavir pharmacokinetic data were available for 37 women without tenofovir, 35 with tenofovir; median (range) pharmacokinetic parameters are presented for second trimester, third trimester, and PP and number who met target/total. ATAZANAVIR WITHOUT TENOFOVIR: AUC 30.5 (9.19-93.8), 45.7 (11-88.3), and 48.8 (9.9-112.2) µg·hr·mL, and 8/14, 29/37, and 27/34 met target. C24 h was 0.49 (0.09-4.09), 0.71 (0.14-2.09), and 0.90 (0.05-2.73) µg/mL; 13/14, 36/37, and 29/34 met target. ATAZANAVIR WITH TENOFOVIR: AUC 26.2 (6.8-60.9) (P < 0.05 compared with PP), 37.7 (0.72-88.2) (P < 0.05 compared with PP), and 58.6 (6-149) µg·hr·mL, and 7/17, 23/32, and 27/29 met target. C24 h was 0.44 (0.12-1.06) (P < 0.05 compared with PP), 0.57 (0.02-2.06) (P < 0.05 compared with PP), and 1.26 (0.09-5.43) µg/mL; 7/17, 23/32, and 27/29 met target. Atazanavir/ritonavir was well tolerated with no unanticipated adverse events. CONCLUSIONS: Atazanavir/ritonavir increased to 400/100 mg provides adequate atazanavir exposure during the third trimester and should be considered during the second trimester.