RESUMEN
BACKGROUND: Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen. METHODS: We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections. RESULTS: Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03). CONCLUSIONS: The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events. (Funded by the National Agency of Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT01473472.).
Asunto(s)
Emtricitabina/uso terapéutico , Infecciones por VIH/prevención & control , VIH-1 , Homosexualidad Masculina , Profilaxis Pre-Exposición , Tenofovir/uso terapéutico , Adulto , Condones/estadística & datos numéricos , Método Doble Ciego , Quimioterapia Combinada , Emtricitabina/efectos adversos , Humanos , Estimación de Kaplan-Meier , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Factores de Riesgo , Conducta Sexual , Enfermedades de Transmisión Sexual/epidemiología , Tenofovir/efectos adversosRESUMEN
BACKGROUND: In the ANRS EASIER trial where treatment-experienced patients switched from enfuvirtide (ENF) to raltegravir (RAL), a high incidence of transaminase elevation was reported in the RAL arm. METHODS: We compared the incidence of emergent liver enzyme elevations (LEE) of grade 2 or more among patients randomized to the maintenance ENF arm or the switch RAL arm up to W24. We also assessed the overall incidence of LEE over the 48-week duration of the trial and baseline risk factors for grade 2 or more alanine aminotransferase (ALT) elevation using univariate and multivariate analyses. RESULTS: During the first 24 weeks, 6/84 (7.1 %) and 2/85 patients (2.4 %) presented with ALT elevation of grade 2 or more in the RAL and ENF arms, respectively (p = 0.21). Grade 2 or more γGT and ALP elevations were seen in 18 and 11 % (p = 0.35), and 5 and 1 % (p = 0.14) of patients in the RAL and ENF arms, respectively. The 48-week incidence of grade 2 or more LEE was 11.6 per 100-pts-years for ALT, 24.5 per 100-pts-years for γ-GT and 4.5 per 100-pts-years for ALP, respectively. In the multivariate analysis, tipranavir/ritonavir use (OR 3.66; 95 % CI [1.20-11.1], p = 0.022) and elevated ALT at baseline (OR 10.3; 95 % CI [2.67-39.6], p < 10(-3)) were significantly associated with a grade 2 or more ALT elevation during follow-up. CONCLUSION: The incidence of LEE was relatively high in these highly treatment-experienced patients switching to a RAL-based regimen. Both tipranavir/ritonavir use and high baseline ALT levels were associated with an increased risk of ALT. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00454337.
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Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Sustitución de Medicamentos/efectos adversos , Proteína gp41 de Envoltorio del VIH/efectos adversos , Inhibidores de Fusión de VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , Fragmentos de Péptidos/efectos adversos , Raltegravir Potásico/efectos adversos , Adulto , Alanina Transaminasa/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfuvirtida , Femenino , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Inhibidores de Fusión de VIH/uso terapéutico , Inhibidores de Integrasa VIH/uso terapéutico , Humanos , Incidencia , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/uso terapéutico , Raltegravir Potásico/uso terapéutico , Factores de RiesgoRESUMEN
BACKGROUND: Few direct anti-hepatitis C virus (HCV) agents have been studied in difficult-to-treat null responder and cirrhotic human immunodeficiency virus (HIV)-coinfected patients. Daclatasvir and asunaprevir combined with pegylated interferon/ribavirin (peg-IFN/RBV) have shown promising results in HCV-monoinfected patients. METHODS: An open-label, single-arm, phase 2 study was conducted in HIV/HCV genotype 1/4-coinfected patients who were null responders to prior peg-IFN/RBV standard therapy and on a raltegravir-based regimen with HIV RNA <400 copies/mL. They received a 4-week lead-in phase with peg-IFN/RBV, followed by 24 weeks of asunaprevir (100 mg twice daily), daclatasvir (60 mg once daily), and peg-IFN/RBV. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12) using intent-to-treat analysis. RESULTS: Seventy-five patients were included, of whom 27 (36%) had cirrhosis. The median baseline CD4 count was 748 (interquartile range, 481-930) cells/µL. The global SVR12 rate was 96.0% (95% confidence interval [CI], 88.8%-99.2%; n = 72/75), 92.6% (95% CI, 75.7%-99.1%; n = 25/27) in cirrhotic patients, 94.6% (95% CI, 81.8%-99.3%; n = 35/37) in genotype 1 patients, and 97.4% (95% CI, 86.2%-99.9%; n = 37/38) in genotype 4 patients. Six patients (8%) stopped HCV therapy prematurely: 2 due to HCV breakthrough, 4 to adverse events (1 lung cancer, 3 infections). One patient with cirrhosis (with baseline platelet count <150 000 platelets/µL and albuminemia <35 g/L) died from multiorgan failure. Overall, 36 serious adverse events occurred in 21 (28%) patients. No HIV breakthrough was observed. CONCLUSIONS: In HIV/HCV genotype 1/4-coinfected null responders, a 24-week regimen combining daclatasvir, asunaprevir, and peg-IFN/RBV was associated with a very high cure rate. The safety profile was acceptable, even though cirrhotic patients with low albuminemia and platelets should be monitored closely. This combination is a new option in this difficult-to-treat population. CLINICAL TRIALS REGISTRATION: NCT01725542.
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Antivirales/uso terapéutico , Coinfección/virología , Infecciones por VIH/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/uso terapéutico , Antivirales/administración & dosificación , Carbamatos , Coinfección/epidemiología , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/virología , Humanos , Imidazoles/administración & dosificación , Masculino , Persona de Mediana Edad , Pirrolidinas , Resultado del Tratamiento , Valina/análogos & derivadosRESUMEN
BACKGROUND: The end-stage LIVER disease and RALtegravir-Agence Nationale de Recherche sur le Sida et les hépatites (LIVERAL-ANRS) 148 study aimed to evaluate the safety, efficacy, and pharmacokinetic parameters of raltegravir (RAL) in human immunodeficiency virus (HIV)-infected patients with end-stage liver disease (ESLD) (substudy 1) and to assess the lack of pharmacokinetic interaction between RAL and the immunosuppressive regimen introduced after liver transplant (substudy 2). METHODS: All patients received 400 mg RAL twice daily plus 2 nucleoside reverse transcriptase inhibitors. Liver function and immunovirological parameters were monitored throughout the study. Serial blood samples were drawn to explore RAL pharmacokinetics. Plasma concentrations of protein unbound, total RAL, and RAL glucuronide were determined by liquid chromatography-tandem mass spectrometry. RESULTS: Ten patients with ESLD were analyzed in substudy 1. Despite an increased RAL exposure, RAL was well tolerated in all patients and no patient had to stop RAL therapy because of adverse events. Four patients were analyzed in substudy 2. No pharmacokinetic interaction was observed between cyclosporine, mycophenolic acid, and RAL. RAL tolerability was excellent; there were no episodes of acute rejection or opportunistic infection. HIV-RNA levels remained controlled and CD4 cell counts remained stable in all patients throughout the study. CONCLUSIONS: The results of the substudy 1 support RAL administration to patients with ESLD. Substudy 2 assesses the safety, tolerability, and efficacy of RAL therapy in HIV-infected patients after liver transplant. RAL might be recommended as a suitable antiretroviral therapy in HIV-infected patients undergoing liver transplant.
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Fármacos Anti-VIH/farmacocinética , Enfermedad Hepática en Estado Terminal , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Plasma/química , Pirrolidinonas/farmacocinética , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Cromatografía Liquida , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinonas/administración & dosificación , Pirrolidinonas/efectos adversos , Raltegravir Potásico , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Espectrometría de Masas en Tándem , Resultado del TratamientoRESUMEN
BACKGROUND: Retreatment with pegylated interferon (peg-IFN) and ribavirin (RBV) results in poor sustained virological response (SVR) rates in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. There are limited data regarding the use of telaprevir plus peg-IFN/RBV in this population. METHODS: HIV type 1-infected patients who previously failed ≥12 weeks of peg-IFN/RBV for HCV genotype 1 coinfection were enrolled in a single-arm, phase 2 trial. Patients with cirrhosis and previous null response were excluded. Authorized antiretrovirals were tenofovir, emtricitabine, efavirenz, atazanavir, and raltegravir. All patients received peg-IFN alfa-2a (180 µg/week) plus RBV (1000-1200 mg/day) for 4 weeks, followed by telaprevir (750 mg or 1125 mg every 8 hours with efavirenz) plus peg-IFN/RBV for 12 weeks and peg-IFN/RBV for 32-56 weeks according to virological response at week 8. The primary endpoint was the SVR rate at 24 weeks after the end of treatment (SVR24). RESULTS: Sixty-nine patients started treatment; SVR24 was achieved in 55 (80% [95% confidence interval, 68%-88%). SVR24 was not influenced by baseline fibrosis stage, IL28B genotype, antiretroviral regimen, HCV subtype, CD4 cell count, previous response to HCV treatment, HCV RNA level, or HCV RNA decline at week 4. HCV treatment was discontinued for adverse events (AEs) in 20% of patients, including cutaneous (4%), psychiatric (4%), hematological (6%), and other AEs (6%). Peg-IFN or RBV dose reduction was required in 23% and 43% of patients, respectively. Seventy percent of patients required erythropoietin, blood transfusions, or RBV dose reduction for anemia. Two patients died during the study. No HIV breakthrough was observed. CONCLUSIONS: Despite a high discontinuation rate related to toxicity, a substantial proportion of treatment-experienced HIV-coinfected patients achieved SVR24 with a telaprevir-based regimen. Clinical Trials Registration. NCT01332955.
Asunto(s)
Antivirales/uso terapéutico , Coinfección/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Oligopéptidos/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Resultado del TratamientoRESUMEN
UNLABELLED: Late onset neonatal sepsis (LOS) has a high mortality and the optimal management is poorly defined. We aimed to evaluate new expert panel-derived criteria to define LOS and characterize the current management and antibiotic susceptibility of LOS-causing organisms in Europe. A prospective observational study enrolled infants aged 4 to 90 days in five European countries. Clinical and laboratory findings as well as empiric treatment were recorded and patients were followed until the end of antibiotic therapy. Failure was defined as a change of primary antibiotic, no resolution of clinical signs, appearance of new signs/pathogens or death. Antibiotic therapy was considered appropriate if the organism was susceptible to at least one empiric antibiotic. 113 infants (median age 14 days, 62 % ≤1500 g) were recruited; 61 % were culture proven cases (28 CoNS, 24 Enterobacteriaceae, 11 other Gram-positives and 6 Gram-negative non-fermentative organisms). The predictive value of the expert-panel criteria to identify patients with a culture proven LOS was 61 % (95 % CI 52 % to 70 %). Around one third of Enterobacteriaceae were resistant to ampicillin + or cefotaxime + gentamicin but only 10 % to meropenem. Empiric treatment contained a total of 43 different antibiotic regimens. All-cause mortality was 8 % with an additional 45 % classified as failure of empiric therapy, mainly due to change of primary antibiotics (42/60). CONCLUSIONS: The expert panel-derived diagnostic criteria performed well identifying a high rate of culture proven sepsis. Current management of LOS in Europe is extremely variable suggesting an urgent need of evidence-based guidelines.
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Antibacterianos/uso terapéutico , Bacteriemia/diagnóstico , Bacteriemia/tratamiento farmacológico , Bacteriemia/microbiología , Bacteriemia/mortalidad , Europa (Continente) , Femenino , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/aislamiento & purificación , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/aislamiento & purificación , Humanos , Lactante , Recién Nacido , Masculino , Pruebas de Sensibilidad Microbiana , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Efavirenz concentrations were measured in 21 patients during an interruption cycle of the ANRS 106 Window trial. The median efavirenz concentrations in the patients 12 h, 3 days, and 7 days after discontinuation of the drug were 1,962 ng/ml, 416 ng/ml, and 112 ng/ml, respectively. The half-life ranged from 27 to 136 h. No relationship between efavirenz exposure and detection of nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations was demonstrated. Patients who were treated by a lamivudine- or emtricitabine-based regimen had a lower risk of NNRTI mutation selection.
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Benzoxazinas/farmacocinética , Desoxicitidina/análogos & derivados , Infecciones por VIH/tratamiento farmacológico , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/genética , Lamivudine/administración & dosificación , Inhibidores de la Transcriptasa Inversa/farmacocinética , Adulto , Alquinos , Sustitución de Aminoácidos , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/farmacocinética , Benzoxazinas/sangre , Cromatografía Líquida de Alta Presión , Ciclopropanos , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Combinación de Medicamentos , Farmacorresistencia Viral , Emtricitabina , Infecciones por VIH/virología , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , Semivida , Humanos , Lamivudine/uso terapéutico , Masculino , Mutación , Inhibidores de la Transcriptasa Inversa/sangre , Carga Viral/efectos de los fármacosRESUMEN
Although predictors of willingness to take daily, self-administered pre-exposure HIV prophylaxis (PrEP) for men who have sex with men (MSM) have been studied in the context of several PrEP trials internationally, little is known about MSM interested in participating in a trial on the use of PrEP on an "on -demand" basis, i.e., taking a first dose of combined tenofovir/emtricitabine a few hours before possible HIV sexual exposure and a second dose a few hours afterwards. A double-blind placebo randomized PrEP trial will soon begin in France to evaluate the effectiveness of PrEP in terms of reducing HIV infection rates, among MSM self-administering "on-demand" PrEP. To assess potential participants' characteristics associated with willingness to participate in the trial and identify barriers and facilitators to implementation, MSM completed a self-administered questionnaire, distributed via gay venues and community websites. Among the 443 respondents who reported being HIV-negative, 40% reported being interested in participating. Factors independently associated with interest included: reporting lower educational level, more than 20 male sexual partners in the previous year, reporting unprotected anal sex with casual partners and preferring PrEP follow-up visits in a devoted area within a hospital. There is great interest in participating in a future "on-demand" PrEP trial among HIV-negative MSM and particularly in those at potentially high risk of HIV exposure. Providing confidentiality and tailored counseling during PrEP follow-up are important issues.
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Quimioprevención/métodos , Infecciones por VIH , Seroclasificación por VIH/psicología , Selección de Paciente , Profilaxis Posexposición/métodos , Sujetos de Investigación/psicología , Adenina/administración & dosificación , Adenina/análogos & derivados , Adulto , Fármacos Anti-VIH/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Combinación de Medicamentos , Escolaridad , Emtricitabina , Francia/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/psicología , Homosexualidad Masculina/psicología , Humanos , Masculino , Organofosfonatos/administración & dosificación , Aceptación de la Atención de Salud/estadística & datos numéricos , Conducta de Reducción del Riesgo , Autoadministración , Tenofovir , Sexo Inseguro/psicologíaRESUMEN
BACKGROUND: Pregnant women and infants who get influenza are at increased risk for severe illness. OBJECTIVE: To evaluate the immunogenicity and transplacental antibody transfer of 2009 pandemic influenza A(H1N1) vaccine administered during pregnancy. DESIGN: Prospective, multicenter, single-group clinical trial. (ClinicalTrials.gov registration number: NCT01024400) SETTING: Five level-3 perinatal centers in France. PATIENTS: 107 pregnant women between 22(0/7) and 32(0/7) weeks of gestation. INTERVENTION: An intramuscular dose of a nonadjuvanted H1N1 vaccine that contained 15 mcg of hemagglutinin. MEASUREMENTS: Proportion of women with an influenza antibody titer of 1:40 or greater at days 21 and 42 after vaccination, delivery, and 3 months after delivery. Seroconversion rate, fold increase in the geometric mean titer 21 days after vaccination, and proportion of neonates with an antibody titer of 1:40 or greater at birth were also assessed. RESULTS: At baseline, 19% of the women had an antibody titer of 1:40 or greater. At day 21, 98% of the women had an antibody titer of 1:40 or greater, the seroconversion rate was 93%, and the fold increase in geometric mean titer was 67.4. At day 42, delivery, and 3 months after delivery, 98%, 92%, and 90% of the women, respectively, had an antibody titer of 1:40 or greater. Ninety-five percent of the cord serum samples obtained from 88 neonates showed an antibody titer of 1:40 or greater. The median neonate-mother antibody titer ratio was 1.4. LIMITATIONS: Only healthy pregnant women were selected. Data on hemagglutination inhibition antibody titers of infants were reported only at birth. CONCLUSION: A single dose of a nonadjuvanted influenza A(H1N1) vaccine with 15 mcg of hemagglutinin triggered a strong immune response in pregnant women and a high rate of neonatal seroprotection. PRIMARY FUNDING SOURCE: French National Institute of Health and Medical Research.
Asunto(s)
Anticuerpos Antivirales/sangre , Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Intercambio Materno-Fetal , Complicaciones Infecciosas del Embarazo/prevención & control , Adolescente , Adulto , Anticuerpos Antivirales/biosíntesis , Femenino , Sangre Fetal/inmunología , Pruebas de Inhibición de Hemaglutinación , Humanos , Recién Nacido , Vacunas contra la Influenza/efectos adversos , Persona de Mediana Edad , Pruebas de Neutralización , Embarazo , Segundo Trimestre del Embarazo/inmunología , Tercer Trimestre del Embarazo/inmunología , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: Human immunodeficiency virus (HIV)-infected patients have decreased immune response to vaccines. Few data are available about pandemic flu vaccination in this population. METHODS: We conducted a multicenter, patient-blinded, randomized trial in a cohort of HIV-infected adults. Patients received 2 injections 21 days apart of a AS03(A)-adjuvanted H1N1v vaccine containing 3.75 µg hemagglutinin (HA) or a nonadjuvanted H1N1v vaccine containing 15 µg HA to assess hemagglutination inhibition (HI) response and safety. RESULTS: A total of 309 patients were randomized, and 306 were vaccinated. After the first vaccine dose, HI titers ≥1:40 were observed in 93.4% of the patients in the adjuvanted group (A group) (n = 155) and in 75.5% in the nonadjuvanted group (B group) (n = 151) (P < .001); seroconversion rates were 88.8% and 71.2%, and factor increases in geometric mean titers (GMT) of 21.9 and 15.1, respectively. After 2 injections, 98.6% of patients of the A group and 92.1% of the B group demonstrated HI titers ≥1:40 (P = .018); seroconversion rates were 96.5% and 87.1%, respectively, and factor increases in GMT were 45.5 and 21.2, respectively. The majority of adverse events were mild to moderate in severity; no impact on CD4+ cell count or viral load has been detected. CONCLUSIONS: In HIV-1-infected adults, the AS03(A)-adjuvanted H1N1v vaccine yielded a higher immune response than did the nonadjuvanted one, with no impact on HIV infection.
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Adyuvantes Inmunológicos/efectos adversos , Infecciones por VIH/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/efectos adversos , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Escualeno/efectos adversos , Adyuvantes Inmunológicos/administración & dosificación , Adulto , Anticuerpos Antivirales/sangre , Femenino , Pruebas de Inhibición de Hemaglutinación , Humanos , Vacunas contra la Influenza/administración & dosificación , Masculino , Persona de Mediana Edad , Escualeno/administración & dosificaciónRESUMEN
We compared tipranavir and darunavir concentrations measured at steady state in 20 human immunodeficiency virus (HIV)-infected patients enrolled in the EASIER-ANRS 138 clinical trial who switched from enfuvirtide to raltegravir while maintaining the same background regimen. The geometric mean ratios of the observed predose concentration (C(trough)), maximum concentration of drug observed in plasma (C(max)), and area under the plasma concentration-time curve (AUC) before (day 0) and after (week 24) the switch were 0.49, 0.76, and 0.67 and 0.82, 0.68, and 0.64 for tipranavir and darunavir, respectively. The virologic consequences of these drug interactions have yet to be determined.
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Fármacos Anti-VIH/farmacocinética , Proteína gp41 de Envoltorio del VIH/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Fragmentos de Péptidos/farmacocinética , Piridinas/farmacocinética , Pironas/farmacocinética , Ritonavir/farmacocinética , Sulfonamidas/farmacocinética , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Darunavir , Enfuvirtida , Femenino , Proteína gp41 de Envoltorio del VIH/sangre , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/sangre , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/uso terapéutico , Piridinas/sangre , Piridinas/uso terapéutico , Pironas/sangre , Pironas/uso terapéutico , Ritonavir/sangre , Ritonavir/uso terapéutico , Sulfonamidas/sangre , Sulfonamidas/uso terapéuticoRESUMEN
OBJECTIVES: To assess the sustainable efficacy and safety of a switch from enfuvirtide to raltegravir in patients with multidrug-resistant HIV infection. METHODS: One hundred and seventy patients with multidrug-resistant HIV infection and suppressed plasma HIV RNA levels < 400 copies/mL under an enfuvirtide-based regimen were randomized to maintain their regimen or to switch to a raltegravir-based regimen (immediate group) in a 48 week prospective, randomized, open-label trial. At week 24, patients in the maintenance arm also switched to raltegravir (deferred group). Baseline genotypic susceptibility scores (GSSs) were calculated using available historical resistance tests. Efficacy was assessed by the cumulative proportion of patients with virological failure, defined as a confirmed plasma HIV RNA ≥ 400 copies/mL up to week 48. The EASIER ANRS 138 trial is registered at ClinicalTrials.gov (NCT00454337). RESULTS: At baseline, 86% of patients had plasma HIV RNA levels <50 copies/mL and 86% had a GSS ≥ 1. Through to week 48, in the on-treatment analysis, only one patient in the immediate group, with a GSS of 0, developed virological failure. At week 48, 90% of patients in both the immediate and deferred groups had plasma HIV-1 RNA levels <50 copies/mL. Median CD4 cell counts remained stable during follow-up. Of note, 12 of 66 (18.2%) patients receiving a regimen combining raltegravir and ritonavir-boosted tipranavir experienced alanine aminotransferase elevations, which led to a switch from tipranavir to darunavir in 8 cases, without discontinuation of raltegravir. CONCLUSIONS: In well-suppressed patients with multidrug-resistant HIV infection, a switch from enfuvirtide to raltegravir is generally well tolerated and has sustained antiviral efficacy when combined with a potent background regimen.
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Proteína gp41 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/uso terapéutico , VIH-1 , Fragmentos de Péptidos/uso terapéutico , Pirrolidinonas/uso terapéutico , Adulto , Alanina Transaminasa/sangre , Recuento de Linfocito CD4 , Farmacorresistencia Viral Múltiple , Determinación de Punto Final , Enfuvirtida , Femenino , Francia , Genotipo , Inhibidores de Fusión de VIH , Infecciones por VIH/sangre , Infecciones por VIH/virología , Inhibidores de Integrasa VIH/efectos adversos , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Pirrolidinonas/efectos adversos , ARN Viral/sangre , Raltegravir Potásico , Resultado del TratamientoRESUMEN
BACKGROUND: among multidrug-resistant HIV-1-infected patients, enfuvirtide has demonstrated sustained efficacy, but long-term use is inconvenient due to twice-daily subcutaneous injections which often induce injection-site reactions. We investigated whether a switch from enfuvirtide to raltegravir, an orally available HIV-integrase inhibitor, may improve health-related quality of life (HRQoL). METHODS: 170 multidrug-resistant HIV-1-infected patients who were receiving enfuvirtide-based regimens were randomised to the maintenance of enfuvirtide or the switch to raltegravir at day 0. At week 24, all patients received raltegravir up to week 48. HRQoL was assessed at baseline and weeks 24 and 48 using a self-report MOS-HIV questionnaire. HRQoL scores were compared between arms using analysis of covariance (ANCOVA) models. RESULTS: at week 24, least-squares means changes from baseline for the maintenance and the substitution arms were -5.3 and +5.8 (P = .001) for the pain score, -4.7 and +4.8 (P = .02) for the social functioning score, and -1.3 and +2.0 (P = .003) for the physical summary score, respectively. CONCLUSION: among multidrug-resistant HIV-1-infected patients, a switch from enfuvirtide to raltegravir resulted in statistically significant improvements in multiple HRQoL dimensions over 24 weeks in comparison to the maintenance under enfuvirtide.
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Proteína gp41 de Envoltorio del VIH/administración & dosificación , Inhibidores de Fusión de VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/administración & dosificación , VIH-1 , Fragmentos de Péptidos/administración & dosificación , Pirrolidinonas/administración & dosificación , Administración Oral , Adulto , Distribución de Chi-Cuadrado , Enfuvirtida , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Infecciones por VIH/psicología , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida/psicología , ARN Viral/sangre , Raltegravir Potásico , Encuestas y CuestionariosRESUMEN
BACKGROUND: In many fields, the choice of a primary endpoint for a trial is not always the ultimate clinical endpoint of interest, but rather some surrogate endpoint believed to be relevant for predicting the effect of the intervention on the clinical endpoint. The classic example of such a field is clinical HIV treatment research, where a variety of primary endpoints are used to evaluate the efficacy of new antiretroviral drugs or new combinations of existing drugs. The choice of endpoint reflects either the goal of therapy as recommended by treatment guidelines (e.g. rapid virological suppression) or the licensing requirements of official drug approval organizations (e.g. time to loss of virological response [TLOVR]). PURPOSE: To review the diversity of endpoints used in recent clinical trials in HIV infection and highlight the methodological issues. METHODS: We identified articles relating to antiretroviral therapy by searching PubMed and through hand searches of relevant conference abstracts. We restricted the search to randomized controlled trials conducted in HIV-infected adults published/presented from January 2005 until March 2008. RESULTS: We identified 28 trials in antiretroviral-naive patients (i.e. patients who were starting antiretroviral therapy for the first time at the time of randomization) and 23 trials in antiretroviral-experienced patients. Most trials were performed for purposes of drug licensing, but others were focused on strategies of using approved drugs. Most trials (40 of 51) used a composite primary endpoint (TLOVR in 13). Of note, 22 of these 40 studies reported that they had used a purely virological efficacy endpoint, but the primary endpoint was actually a composite one due to the way in which missing data and treatment switches were considered as failures. LIMITATIONS: Examples are restricted to HIV clinical trials. CONCLUSIONS: Whilst most current HIV clinical trials use composite primary endpoints, there are substantial differences in the components that make up these endpoints. In HIV and other fields where precise definitions are variable, guidelines for standardization of definition and reporting would greatly improve the ability to compare trial results.
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Determinación de Punto Final , Infecciones por VIH/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Terapia Antirretroviral Altamente Activa , Biomarcadores , Humanos , Resultado del TratamientoRESUMEN
BACKGROUND: The early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged <90 days with LOS. METHODS AND FINDINGS: NeoMero-1 was a randomized, open-label, phase III superiority trial conducted in 18 neonatal units in 6 countries. Infants with post-menstrual age (PMA) of ≤44 weeks with positive blood culture and one, or those with negative culture and at least with two predefined clinical and laboratory signs suggestive of LOS, or those with PMA >44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052). CONCLUSIONS: Within this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating.
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Meropenem/uso terapéutico , Sepsis Neonatal/tratamiento farmacológico , Nivel de Atención , Femenino , Humanos , Lactante , Masculino , Meropenem/efectos adversos , Seguridad , Resultado del TratamientoRESUMEN
BACKGROUND: Among patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection, salvage regimens including enfuvirtide have demonstrated sustained efficacy. Because of reluctance to use subcutaneous injections, raltegravir may be an alternative to replace enfuvirtide within a suppressive regimen. We conducted a prospective, randomized, open-label trial to compare the antiviral efficacy and safety of a switch to raltegravir with the efficacy and safety of continuing enfuvirtide. METHODS: A total of 170 patients with multidrug-resistant HIV-1 infection and plasma HIV-1 RNA levels <400 copies/mL who were receiving enfuvirtide-based regimens were randomized 1:1 to maintain enfuvirtide or to switch to raltegravir. The primary efficacy end point was the cumulative proportion of patients with virologic failure, defined as a confirmed plasma HIV-1 RNA level >or=400 copies/mL, over 24 weeks. The secondary end points mainly involved safety. RESULTS: The switch to raltegravir was non-inferior to the maintenance of enfuvirtide, with virologic failure rates of 1.2% in both treatment arms in the intention-to-treat analysis (beta = 0.01%; 95% confidence interval, -6.7 to 6.8) and 1.2% and 0%, respectively, in the on-treatment analysis (beta = 1.22%; 95% confidence interval, -5.6 to 8.1). At week 24, 88%-89% of patients in both arms had plasma HIV-1 RNA levels <50 copies/mL. No significant CD4 cell count changes occurred in either arm. Grade 3-4 adverse events and laboratory abnormalities were uncommon and were not different between the treatment arms. CONCLUSION: A switch to raltegravir was safe, well tolerated, and virologically non-inferior to the maintenance of enfuvirtide in patients infected with multidrug-resistant HIV-1 infection who were receiving suppressive antiretroviral therapy. CLINICAL TRIALS REGISTRATION: NCT00454337
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Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral Múltiple , Proteína gp41 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Fragmentos de Péptidos/uso terapéutico , Pirrolidinonas/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , Enfuvirtida , Femenino , Proteína gp41 de Envoltorio del VIH/efectos adversos , VIH-1/efectos de los fármacos , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/efectos adversos , Pirrolidinonas/efectos adversos , ARN Viral/sangre , Raltegravir Potásico , Resultado del Tratamiento , Carga ViralRESUMEN
OBJECTIVES: We evaluate the efficacy and tolerability of ritonavir-boosted dual protease inhibitor as a nucleoside reverse transcriptase inhibitor-sparing regimen in a prospective open-label randomized pilot trial in antiretroviral-naive patients. METHODS: Thirty patients received fosamprenavir/atazanavir/ritonavir (Group 1) and 31 patients received saquinavir/atazanavir/ritonavir (Group 2). The primary endpoint for efficacy was the rate of early virological success, defined as plasma viral load <50 copies/mL at week 16. The study is registered with ClinicalTrials.gov (NCT00122603). RESULTS: At baseline, median (range) viral load was 4.8 log(10) copies/mL (4.0-5.7) and the median CD4 cell count was 271/mm(3) (197-740). Viral load was <50 copies/mL in 12/30 patients [40%, 95% confidence interval (CI) 23%-58%] and 13/31 patients (42%, 95% CI 25%-59%) at week 16 in Groups 1 and 2, respectively. Patients with failing regimens (viral load >or=400 copies/mL at week 16 or >or=50 copies/mL at week 24) were switched to a standard antiretroviral regimen. At week 48, by an intention-to-treat analysis, 23/30 patients (77%) and 26/31 patients (84%) had plasma HIV-1 RNA <50 copies/mL in Groups 1 and 2, respectively. Four patients discontinued treatment for adverse events, all before week 4. No major changes in the protease gene were detected at treatment failure relative to baseline. Baseline viral load <50 000 copies/mL was the only predictor of virological success at week 16. CONCLUSIONS: Ritonavir-boosted dual protease inhibitor regimens targeting only one step of viral replication were insufficient to rapidly suppress plasma HIV RNA to <50 copies/mL in antiretroviral-naive patients with high viral load at baseline.
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Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/efectos de los fármacos , Ritonavir/efectos adversos , Ritonavir/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/efectos adversos , Asparagina/efectos adversos , Asparagina/análogos & derivados , Asparagina/uso terapéutico , Sulfato de Atazanavir , Recuento de Linfocito CD4 , Carbamatos/efectos adversos , Carbamatos/uso terapéutico , Femenino , Furanos , Humanos , Masculino , Persona de Mediana Edad , Oligopéptidos/efectos adversos , Oligopéptidos/uso terapéutico , Organofosfatos/efectos adversos , Organofosfatos/uso terapéutico , Piridinas/efectos adversos , Piridinas/uso terapéutico , Quinolinas/efectos adversos , Quinolinas/uso terapéutico , ARN Viral/sangre , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Resultado del Tratamiento , Carga ViralRESUMEN
PURPOSE: To study the impact of baseline resistance mutations and HIV-1 subtypes on virological response to first-line antiretroviral therapy and to analyse the concordance of the results of two antiretroviral resistance interpretation tools in the INITIO trial. METHOD: Genotype and virco TYPE resistance analyses were studied at baseline, Year 2, Year 3, and at first therapeutic failure on plasma specimens stored at -80 degrees C. Relations between resistance mutations at baseline, subtype, initial virological response, and virological outcome after Week 24 were studied. RESULTS: 781 participants had genotypic results available at baseline. Therapeutic failure occurred for 112 participants. Initial virological response as well as virological outcome after Week 24 were not associated with HIV subtype. Before Week 24, the proportion of participants remaining under strict initial regimen was lower in patients with resistance mutations at baseline than in those without any resistance mutations. Presenceof resistance mutations at baseline also impacted negatively long-term virological outcome. Few discrepancies were observed between genotypic and virco TYPE for resistance interpretation. CONCLUSION: These data showed that presence of resistance mutations at baseline was associated with a poorer long-term virological outcome in the INITIO trial.
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Farmacorresistencia Viral Múltiple/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1 , Alquinos , Benzoxazinas/administración & dosificación , Ciclopropanos , Didanosina/administración & dosificación , Quimioterapia Combinada , Femenino , Genoma Viral , Infecciones por VIH/sangre , Inhibidores de la Proteasa del VIH/administración & dosificación , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Masculino , Mutación , Nelfinavir/administración & dosificación , ARN Viral/sangre , ARN Viral/efectos de los fármacos , ARN Viral/genética , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Estavudina/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Virología/métodosRESUMEN
The Task-force in Europe for Drug Development for the Young (TEDDY) was established in 2005 to contribute to the promotion of safe and efficacious medicines for children in the context of the impending European Paediatric Regulation that finally came into force in January 2007. The project includes seven objectives and 12 Work-Packages encompassing the main aspects of the development and use of pediatric drugs. TEDDY represents a new entity in the pediatric pharmaceutical field, differing from a Scientific Society, a network for developing research or trials, or a consultative regulatory body. The ambition of TEDDY is to support the existing pediatric networks, societies, and regulatory bodies in performing innovative initiatives, including those in areas in which such undertakings would not be feasible without supportive action. To accomplish its aim, TEDDY has focused on three different actions: (i) increasing awareness about the Paediatric Regulation revolution; (ii) reaching consensus on terms and instruments to be used for common research; and (iii) favoring close relationships among different stakeholders and partners from different EU Member States. After 3 years of activities, many results have been produced by the Network: surveys, databases, expert opinions, and recommendations. Linking together different stakeholders, including industry and patient associations, as well as academia and research centers, the Network has contributed to increasing awareness and participation in the Paediatric Regulation. In addition, many papers detailing original results have either been published or submitted for publication in peer-reviewed journals. TEDDY is an original Network whose identity and role as a catalyzer of initiatives related to the use and development of pediatric drugs needs to be better clarified in the near future. Of particular importance is the need to reach consensus on best practices. The lack of a common view on pediatric research requirements among stakeholders across Member States remains the main challenge to be overcome.
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Comités Consultivos/organización & administración , Aprobación de Drogas/legislación & jurisprudencia , Quimioterapia/estadística & datos numéricos , Adolescente , Niño , Preescolar , Bases de Datos Factuales , Europa (Continente) , Agencias Gubernamentales , Humanos , Lactante , Recién Nacido , PediatríaRESUMEN
BACKGROUND: We aimed here to study drug-associated HIV resistance mutations in peripheral blood mononuclear cells (PBMC) and plasma during intermittent therapy. METHODS: A substudy of 86 patients randomized to the intermittent treatment arm (8-week on/8-week off) of the ANRS 106 Window trial. HIV reverse transcriptase and protease genes were sequenced and resistance mutations identified according to the International AIDS Society list. RESULTS: Resistance mutations were detected in PBMC of 27/86 (31%) patients at baseline and 25/72 (35%) patients at week 96. Resistance mutations were detected in plasma of 28/86 (33%), 24/83 (29%) and 33/80 (41%) patients at weeks 8, 40 and 88, respectively. The detection of nucleoside reverse transcriptase inhibitor and protease inhibitor associated resistance mutations in plasma remained stable over time, but there was an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations in patients on an NNRTI-based regimen: 1/33 (3%) versus 7/26 patients (27%) at weeks 8 and 88, respectively (P=0.02). The proportions of patients with plasma HIV RNA levels < or =400 copies/ml after 8 weeks of treatment at weeks 16, 48 and 96 in patients with drug-resistant and wild-type viruses were 93% versus 74% (P=0.04), 96% versus 88% (P=0.43) and 70% versus 84% (P=0.13), respectively. Patients with drug-resistant virus had a lower CD4+ T-cell decrease from baseline at weeks 40 and 88 as compared to patients with wild-type virus (P=0.05 and 0.002, respectively). CONCLUSIONS: NNRTI-associated resistance mutations increased over time in plasma of patients who were given NNRTIs. Drug-associated HIV resistance mutations did not seem to impair short-term antiviral response and might be associated with reduced CD4' T-cell loss during interruptions.