RESUMEN
BACKGROUND & AIMS: The combination of vaniprevir (a NS3/4A protease inhibitor) with peginterferon and ribavirin was shown to increase rates of sustained virologic response (SVR) significantly, compared with peginterferon and ribavirin alone, in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection without cirrhosis. We performed a blinded, randomized, controlled trial of the effects of vaniprevir with peginterferon and ribavirin in patients with cirrhosis who did not respond to prior therapy with peginterferon and ribavirin. METHODS: Treatment-experienced patients (88% white and 35% prior null responders) with HCV genotype 1 infection and compensated cirrhosis were assigned randomly to groups given vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 24 weeks (n = 16), vaniprevir (600 mg twice daily) for 24 weeks with peginterferon and ribavirin for 48 weeks (n = 14), vaniprevir (300 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), or placebo with peginterferon and ribavirin for 48 weeks (n = 14, control). Cirrhosis was documented by liver biopsy (84%) or noninvasive methods (16%). Before randomization, participants were stratified based on their historical response to peginterferon and ribavirin. RESULTS: In the primary analysis, SVR rates among patients in the respective vaniprevir groups were 9 of 15 (60.0%), 9 of 13 (69.2%), 8 of 15 (53.3%), and 10 of 13 (76.9%), compared with 2 of 14 (14.3%) in the control group (pairwise P values ≤ .016). Cirrhotic patients with null or partial responses to prior therapy achieved SVR less often than patients with prior breakthrough or relapse, although 42.1% of prior null responders in the vaniprevir groups achieved SVRs. Patients in the vaniprevir groups more frequently experienced mild-moderate nausea, vomiting, and diarrhea than controls; 5% developed grade 2 anemia compared with none in the control group (no patient developed grade 3 or 4 anemia). Among patients in the vaniprevir groups who experienced virologic failure, resistance-associated variants were detected predominantly at positions 155, 156, and 168 in the HCV protease gene. CONCLUSIONS: In a controlled phase 2B trial, vaniprevir with peginterferon and ribavirin significantly increased rates of SVR among treatment-experienced patients with chronic HCV genotype 1 infection, compared with re-treatment with peginterferon and ribavirin alone. Vaniprevir generally was well tolerated for up to 48 weeks in patients with compensated cirrhosis. ClinicalTrials.gov number, NCT00704405.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Indoles/uso terapéutico , Interferón-alfa/uso terapéutico , Cirrosis Hepática , Ribavirina/uso terapéutico , Carga Viral , Adolescente , Adulto , Anciano , Ciclopropanos , Método Doble Ciego , Quimioterapia Combinada/métodos , Femenino , Genotipo , Hepacivirus/clasificación , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Isoindoles , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Prolina/análogos & derivados , Sulfonamidas , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: In the international, placebo-controlled, Rotavirus Efficacy and Safety Trial, the pentavalent rotavirus vaccine reduced the rate of rotavirus-attributable hospitalizations and emergency department visits by 95%. This study investigated the effect in Jamaica. METHODS: The vaccine effect on rates of hospitalizations and emergency department visits in Jamaica was evaluated in both modified intention-to-treat and per-protocol analyses. Rates of serious adverse events, including intussusception, also were compared between groups. RESULTS: A total of 1804 Jamaican infants, 6 to 12 weeks of age at entry and primarily from low/middle-income families of African heritage, received ≥1 dose. During the first year after dose 1, there were 2 and 11 hospitalizations or emergency department visits attributable to rotavirus gastroenteritis involving any serotype among 831 evaluable vaccine recipients and 809 evaluable placebo recipients, respectively (rate reduction: 82.2% [95% confidence interval: 15.1%-98.0%]). In the per-protocol analysis, all 8 G1 to G4 rotavirus-attributable events that occurred ≥2 weeks after dose 3 were in the placebo group (rate reduction: 100% [95% confidence interval: 40.9%-100%]). Of the 1802 subjects included in the safety analyses, intussusception was confirmed for 1 vaccine recipient (115 days after the third dose) and 3 placebo recipients. One vaccine recipient and 3 placebo recipients died during the follow-up period, but none of the deaths was considered to be vaccine-related. CONCLUSIONS: In this posthoc subgroup analysis, the vaccine reduced health care resource utilization attributable to rotavirus gastroenteritis, without increased risk of intussusception or other serious adverse events, among infants in a resource-limited country.
Asunto(s)
Atención a la Salud/estadística & datos numéricos , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/administración & dosificación , Rotavirus/inmunología , Países en Desarrollo , Femenino , Estudios de Seguimiento , Hospitalización/estadística & datos numéricos , Humanos , Lactante , Jamaica/epidemiología , Masculino , Estudios Retrospectivos , Infecciones por Rotavirus/epidemiología , Infecciones por Rotavirus/inmunología , Resultado del Tratamiento , Vacunas Atenuadas/administración & dosificaciónRESUMEN
BACKGROUND: A live pentavalent rotavirus vaccine (PRV) containing 5 human-bovine (WC3) reassortants expressing human serotypes G1, G2, G3, G4 and P1A[8] was evaluated in a blinded, placebo-controlled study. Possible interactions between PRV and concomitantly administered licensed pediatric vaccines were investigated in a United States-based nested substudy (Concomitant Use Study) of the Rotavirus Efficacy and Safety Trial. METHODS: From 2002 to 2003, healthy infants approximately 6 to 12 weeks of age at entry were randomized to receive either 3 oral doses of PRV or placebo at 4- to 10-week intervals. Subjects were also to receive combined Haemophilus influenzae type b and hepatitis B vaccine (2 doses), diphtheria and tetanus toxoids and acellular pertussis vaccine (3 doses), inactivated poliovirus vaccine (2 doses) and pneumococcal conjugate vaccine (3 doses) on the same day; oral poliovirus vaccine was not administered. Immunogenicity was assessed by measuring antibody responses to PRV and antigens contained in the licensed vaccines. Cases of rotavirus gastroenteritis were defined by forceful vomiting and/or -3 watery or looser-than-normal stools within a 24-hour period, and detection of rotavirus antigen in the stool. Safety was assessed by reporting of adverse events using diary cards. RESULTS: The Concomitant Use Study enrolled 662 subjects in the PRV group and 696 subjects in the placebo group. For the 17 antigens in the concomitantly administered vaccines, antibody responses were similar in PRV and placebo recipients, except for moderately diminished antibody responses to the pertactin component of pertussis vaccine. Efficacy of PRV against rotavirus gastroenteritis of any severity was 89.5% (95% CI = 26.5-99.8%). PRV was generally well tolerated when given concomitantly with the prespecified vaccines. CONCLUSIONS: In this study, antibody responses to the concomitantly administered vaccines were generally similar in PRV and placebo recipients. PRV was efficacious and well tolerated when given concomitantly with pediatric vaccines licensed in the United States.
Asunto(s)
Virus Reordenados/inmunología , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/inmunología , Rotavirus/inmunología , Administración Oral , Animales , Anticuerpos Antivirales/sangre , Bovinos , Vacuna contra Difteria, Tétanos y Tos Ferina/administración & dosificación , Vacuna contra Difteria, Tétanos y Tos Ferina/efectos adversos , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Método Doble Ciego , Esquema de Medicación , Femenino , Vacunas contra Haemophilus/administración & dosificación , Vacunas contra Haemophilus/efectos adversos , Vacunas contra Haemophilus/inmunología , Vacunas contra Hepatitis B/administración & dosificación , Vacunas contra Hepatitis B/efectos adversos , Vacunas contra Hepatitis B/inmunología , Humanos , Lactante , Masculino , Vacunas Neumococicas/administración & dosificación , Vacunas Neumococicas/efectos adversos , Vacunas Neumococicas/inmunología , Vacuna Antipolio de Virus Inactivados/administración & dosificación , Vacuna Antipolio de Virus Inactivados/efectos adversos , Vacuna Antipolio de Virus Inactivados/inmunología , Vacunas contra Rotavirus/efectos adversos , Estados UnidosRESUMEN
OBJECTIVES: SMART (Study for Monitoring Antimicrobial Resistance Trends) is an ongoing study to monitor worldwide antimicrobial resistance trends among aerobic and facultatively anaerobic Gram-negative bacilli (GNB) isolated from intra-abdominal infections. This 2004 report summarizes the most recently completed annual data from SMART. METHODS: During 2004, 81 medical centres from 28 countries in five global regions collected intra-abdominal GNB for antimicrobial susceptibility testing using broth microdilution according to the Clinical and Laboratory Standards Institute guidelines. RESULTS: A total of 6156 unique aerobic and facultatively anaerobic GNB were isolated from intra-abdominal infections. Enterobacteriaceae composed 86% of the total isolates. Among the 12 antimicrobial agents tested, the carbapenems and amikacin were the most consistently active against the Enterobacteriaceae. Escherichia coli was the most commonly isolated species (48%), and the susceptibility rate to the quinolones was lowest in Asia/Pacific and Latin America. Extended-spectrum beta-lactamases (ESBLs) were detected phenotypically in 10% of E. coli, 17% of Klebsiella spp. and 22% of Enterobacter spp. worldwide, representing a slight increase over the two previous years. ESBL producers typically had a more antibiotic-resistant profile than non-ESBL producers but were usually susceptible to the carbapenems. CONCLUSIONS: Antimicrobial resistance among GNB isolated from intra-abdominal infections continued to be a problem worldwide in 2004, with the highest rates of resistance overall in the Asia/Pacific region. The carbapenems and amikacin were the most consistently active agents in vitro against Enterobacteriaceae isolated from intra-abdominal infections worldwide.
Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/epidemiología , Infecciones por Bacterias Gramnegativas/microbiología , Abdomen/microbiología , HumanosRESUMEN
BACKGROUND: Candida esophagitis remains an important cause of morbidity in patients with advanced human immunodeficiency virus (HIV) infection. Fluconazole is widely regarded as the treatment of choice for this condition. METHODS: The efficacy and safety of caspofungin were compared with fluconazole in adult patients with Candida esophagitis in a double-blind randomized trial. Eligible patients had symptoms compatible with esophagitis, endoscopic demonstration of mucosal plaques, and microscopic demonstration of Candida from the esophageal lesions. Patients were randomly assigned to receive caspofungin (50 mg) or fluconazole (200 mg) intravenously once daily for 7 to 21 days. The primary endpoint was the combined response of symptom resolution and significant endoscopic improvement 5 to 7 days after discontinuation of treatment. Data were analyzed with a modified intention-to-treat analysis, which excluded 2 ineligible patients. RESULTS: Most patients (154/177; 87%) had HIV infection, with a median CD4 count of 30 cells/mm(3). Candida albicans was the predominant isolate. Favorable response rates were achieved in 66 (81%) of the 81 patients in the caspofungin arm and in 80 (85%) of the 94 patients in the fluconazole arm (difference = -4%; 95% confidence interval: -15% to +8%). Symptoms had resolved in >50% of patients in both groups by the fifth day of treatment. No patient in the caspofungin group developed a serious drug-related adverse event; therapy was only discontinued in 1 patient (receiving fluconazole) due to a drug-related adverse experience. Four weeks after stopping study drug, symptoms had recurred in 18 (28%) of 64 patients given caspofungin and in 12 (17%) of 72 patients given fluconazole (P = 0.19). CONCLUSIONS: In this study, caspofungin appeared to be as efficacious and generally as well tolerated as fluconazole in patients with advanced HIV infection and documented Candida esophagitis.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Antibacterianos/uso terapéutico , Antifúngicos/uso terapéutico , Candidiasis Bucal/tratamiento farmacológico , Esofagitis/tratamiento farmacológico , Fluconazol/uso terapéutico , Péptidos Cíclicos , Péptidos , Infecciones Oportunistas Relacionadas con el SIDA/patología , Adolescente , Adulto , Anciano , Antibacterianos/administración & dosificación , Antifúngicos/administración & dosificación , Candidiasis Bucal/patología , Caspofungina , Chile , Método Doble Ciego , Esquema de Medicación , Equinocandinas , Esofagitis/patología , Esofagoscopía , Femenino , Fluconazol/administración & dosificación , Guatemala , Humanos , Infusiones Intravenosas , Lipopéptidos , Masculino , Persona de Mediana Edad , Pennsylvania , Perú , Resultado del TratamientoRESUMEN
Caspofungin is an antifungal agent of the novel echinocandin class. We investigated its efficacy, safety, and tolerability as therapy for oropharyngeal and/or esophageal candidiasis in a phase II dose-ranging study. Patients were randomized in a double-blind manner to receive either caspofungin acetate (35, 50, or 70 mg) or amphotericin B (0.5 mg/kg of body weight) intravenously once daily for 7 to 14 days. A favorable response required both complete resolution of symptoms and quantifiable improvement of mucosal lesions 3 to 4 days after discontinuation of study drug. Efficacy was assessed using a modified intent-to-treat analysis. No hypothesis testing of efficacy was planned or performed. Of 140 enrolled patients, 63% had esophageal involvement and 98% were infected with the human immunodeficiency virus (HIV) (median CD4 count, 30/mm(3)). A modestly higher proportion of patients in each of the caspofungin groups (74 to 91%) achieved favorable responses compared to amphotericin B recipients (63%), but there was considerable overlap in the 95% confidence intervals surrounding these point estimates. Similar trends were found in the subgroups with esophageal involvement, a history of fluconazole failure, and CD4 counts of < or =50/mm(3). A smaller proportion of patients receiving any dose of caspofungin experienced drug-related adverse events compared to patients given standard doses of conventional amphotericin B (P < 0.01). Caspofungin provided a generally well-tolerated parenteral therapeutic option for HIV-infected patients with oropharyngeal and/or esophageal candidiasis in this study.