RESUMEN
BACKGROUND: The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known. METHODS: In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru. RESULTS: A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose. CONCLUSIONS: AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).
Asunto(s)
COVID-19/prevención & control , ChAdOx1 nCoV-19 , Eficacia de las Vacunas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , COVID-19/epidemiología , ChAdOx1 nCoV-19/efectos adversos , Chile/epidemiología , Método Doble Ciego , Femenino , Humanos , Inmunogenicidad Vacunal , Masculino , Persona de Mediana Edad , Perú/epidemiología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Estados Unidos/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: To compare the efficacy, safety, and anti-inflammatory effects of cenicriviroc (CVC), an oral, once-daily C-C chemokine receptor types 5 and 2 antagonist, with those of efavirenz (EFV) in treatment-naive, HIV-1-infected adults. DESIGN: A 48-week, randomized, double-blind, double-dummy phase 2b trial at 43 institutions (USA and Puerto Rico). METHODS: Study participants (HIV-1 RNA ≥1000 copies/ml, CD4 cell count ≥200 cells/µl, C-C chemokine receptor type 5-tropic virus) were randomized 2â:â2â:â1 to CVC 100âmg (CVC100), CVC 200âmg (CVC200), or EFV 600âmg, each administered with emtricitabine/tenofovir disoproxil fumarate. Key end points were virologic success (HIV-1 RNA <50 copies/ml) at week 24 (primary) and week 48 (secondary), safety/tolerability at weeks 24 and 48. Study sites and patients remained blinded until week 48. RESULTS: A total of 143 patients were randomized (CVC100, nâ=â59; CVC200, nâ=â56; EFV, nâ=â28). Virologic success was obtained at week 24 in 76, 73, and 71% of study participants for CVC100, CVC200, and EFV, respectively (all Pâ>â0.05 versus EFV), and at week 48 in 68, 64, and 50%, respectively (all Pâ>â0.05 versus EFV). Resistance mutations emerged in five and zero CVC and EFV-treated study participants, respectively. Virologic nonresponse and nucleoside reverse transcriptase inhibitor resistance decreased when CVC minimum plasma concentration was at least 47.8âng/ml. Treatment-related adverse events of at least grade 2 and discontinuations because of adverse events were less frequent in CVC-treated study participants. Total and low-density lipoprotein cholesterol decreased with CVC, but increased with EFV. C-C chemokine ligand type 2 (CCL2) (aka monocyte chemotactic protein-1) increased in a dose-dependent manner, whereas soluble CD14 levels decreased with CVC. CONCLUSION: CVC showed efficacy and favorable safety in treatment-naive HIV-1-infected study participants, supporting selection of CVC200 for phase 3 studies. TRIAL REGISTRATION: NCT01338883.
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Fármacos Anti-VIH/administración & dosificación , Benzoxazinas/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Imidazoles/administración & dosificación , Receptores CXCR5/antagonistas & inhibidores , Tropismo Viral , Adulto , Alquinos , Fármacos Anti-VIH/efectos adversos , Benzoxazinas/efectos adversos , Ciclopropanos , Método Doble Ciego , Femenino , Genotipo , VIH-1/clasificación , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Imidazoles/efectos adversos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Masculino , Persona de Mediana Edad , Puerto Rico , Receptores del VIH/antagonistas & inhibidores , Sulfóxidos , Resultado del Tratamiento , Estados Unidos , Carga Viral , Adulto JovenRESUMEN
BACKGROUND & AIMS: Sofosbuvir (formerly GS-7977) is a pyrimidine nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B polymerase. We assessed the safety, tolerability, antiviral activity, and pharmacokinetics of sofosbuvir plus pegylated-interferon (PegIFN)/ribavirin (RBV) in a 28-day, dose-ranging trial in treatment-naïve patients infected with genotype 1 HCV. METHODS: In this double-blind study, 64 patients were randomized (1:1:1:1) to receive one of three once-daily doses of oral sofosbuvir (100, 200, or 400mg) or placebo plus PegIFN/RBV for 28 days, after which all patients continued to receive PegIFN/RBV alone for a further 44 weeks. RESULTS: Patients in the sofosbuvir/PegIFN/RBV groups experienced mean reductions in HCV RNA >5 log10 IU/ml (-5.3 for 100 mg, -5.1 for 200 mg and -5.3 for 400 mg) vs. -2.8 log10 IU/ml for placebo/PegIFN/RBV after 28 days. Rapid virologic response (RVR) rates were markedly higher after sofosbuvir treatment (88-94%) than placebo (21%), as were rates of sustained virologic response (SVR) at post-treatment Week 24 (56%, 83%, and 80% for sofosbuvir 100, 200, and 400 mg, respectively, vs. 43% for placebo). The number of patients experiencing virologic breakthrough and post-treatment relapse was higher in the sofosbuvir 100 mg group than sofosbuvir 200 and 400 mg groups. Sofosbuvir was well tolerated; the most frequent adverse events were fatigue and nausea. CONCLUSIONS: These results support further studies with sofosbuvir at 200 mg and 400 mg to determine the optimal dose and treatment duration of sofosbuvir in HCV genotype 1.
Asunto(s)
Antivirales/administración & dosificación , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Interferón-alfa/administración & dosificación , Polietilenglicoles/administración & dosificación , Ribavirina/administración & dosificación , Uridina Monofosfato/análogos & derivados , Adulto , Antivirales/efectos adversos , Antivirales/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Hepacivirus/clasificación , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Sofosbuvir , Factores de Tiempo , Resultado del Tratamiento , Uridina Monofosfato/administración & dosificación , Uridina Monofosfato/efectos adversos , Uridina Monofosfato/farmacocinética , Adulto JovenRESUMEN
A randomized, open-label, multicenter study was conducted to evaluate the therapeutic switch to a single-tablet formulation of efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF) among virologically suppressed, HIV-1-infected subjects. Eligible subjects on stable antiretroviral therapy (ART) with HIV-1 RNA less than 200 copies per milliliter for 3 months or more were stratified by prior protease inhibitor (PI)- or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy and randomized (2:1) to EFV/FTC/TDF or to stay on their baseline regimen (SBR). Patient-reported measures were quality of life (QOL; SF-36 [version 2]), treatment adherence (visual analogue scale), preference of medication (POM), perceived ease of the regimen for condition (PERC), and a 20-item HIV symptom index. Overall, 203 subjects were randomized to EFV/FTC/TDF and 97 to SBR. Fifty-three percent of subjects had previously received a PI-based regimen; 47% an NNRTI-based therapy. Throughout the study, SF-36 summary scores did not differ significantly from baseline, regardless of previous ART or treatment allocation. Adherence was 96% or more in both groups at baseline and all subsequent study visits. At study conclusion, the EFV/FTC/TDF regimen was considered easier to follow than prior regimens by 97% and 96% of subjects previously receiving PI-based and NNRTI-based therapies, respectively. Overall, 91% of subjects switched to EFV/FTC/TDF indicated a preference over their prior therapy. Switching to EFV/FTC/TDF was associated with transient worsening/emergence of dizziness and sustained improvements in several other HIV-related symptoms. In conclusion, switching virologically suppressed, HIV-1-infected subjects from PI-based or NNRTI-based regimens to EFV/FTC/TDF was associated with maintained QOL and treatment adherence, and improved ease of use and treatment satisfaction.
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Adenina/análogos & derivados , Fármacos Anti-VIH , Benzoxazinas , Desoxicitidina/análogos & derivados , Infecciones por VIH/tratamiento farmacológico , Organofosfonatos , Inhibidores de la Transcriptasa Inversa , Adenina/administración & dosificación , Adenina/efectos adversos , Adenina/uso terapéutico , Adolescente , Alquinos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/administración & dosificación , Benzoxazinas/efectos adversos , Benzoxazinas/uso terapéutico , Ciclopropanos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Esquema de Medicación , Quimioterapia Combinada , Emtricitabina , Femenino , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Humanos , Masculino , Organofosfonatos/administración & dosificación , Organofosfonatos/efectos adversos , Organofosfonatos/uso terapéutico , Cooperación del Paciente , Prioridad del Paciente , Puerto Rico , Calidad de Vida , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Índice de Severidad de la Enfermedad , Comprimidos/administración & dosificación , Comprimidos/uso terapéutico , Tenofovir , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: Agents that block the CCR5 coreceptor for human immunodeficiency virus (HIV) have demonstrated potent antiretroviral activity. In early clinical studies, the CCR5 antagonist vicriviroc proved to be a safe and effective component of combination antiretroviral therapy. METHODS: This double-blind, dose-ranging, phase 2 trial randomized subjects to receive 30 mg or 20 mg of vicriviroc or placebo once daily plus re-optimized background therapy containing a protease inhibitor with ritonavir. Subjects were adults infected with CCR5-tropic HIV who were experiencing failure of triple antiretroviral regimens. The primary end point was mean change in baseline log(10) HIV RNA level at 48 weeks, based on an intent-to-treat analysis. RESULTS: One hundred fourteen persons received vicriviroc at 30 mg (n = 39), vicriviroc at 20 mg (n =40), or placebo (n = 35). The mean change in baseline HIV RNA level at week 48 was -1.77 log(10) copies/mL for 30 mg of vicriviroc and -1.75 log(10) copies/mL for 20 mg of vicriviroc, compared with -0.79 log(10) copies/mL for placebo (P =.002 and P=.003, respectively, compared with placebo). Mean CD4 counts increased by 102, 136, and 63 cells/mm(3) for 30 mg vicriviroc, 20 mg vicriviroc, and placebo, respectively (P = .260 and P = .039, respectively, compared with placebo). Rates of adverse events (mostly mild-to-moderate) were 111.4, 112.5, and 147.4 events per 100 subject-years, respectively. CONCLUSIONS: Vicriviroc administered with a protease inhibitor plus ritonavir-containing regimen shows potent antiretroviral and immunologic activity sustained over 48 weeks in treatment-experienced patients. CLINICAL TRIALS REGISTRATION: NCT00243230 .
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , Antagonistas de los Receptores CCR5 , Recuento de Linfocito CD4 , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/efectos adversos , Pirimidinas/efectos adversos , ARN Viral/sangre , Ritonavir/uso terapéutico , Carga ViralRESUMEN
BACKGROUND: Abacavir (ABC) and lamivudine (3TC) administered twice daily were compared with an ABC + 3TC fixed-dose combination (Epzicom, Kivexa; EPZ) administered once daily, both in combination with a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI). METHODS: Two hundred sixty HIV-infected subjects with more than 6 months of ABC and 3TC administered twice daily plus a PI or NNRTI with an HIV-1 RNA level less than 400 copies/mL for more than 3 months and a CD4 count greater than 50 cells/mm were randomized 1:1 to ABC + 3TC administered twice daily or EPZ administered once daily. RESULTS: At baseline, median time on ABC and 3TC administered twice daily was 22 months, and median CD4 count and HIV-1 RNA level were 554 cells/mm and <50 copies/mL, respectively. EPZ administered once daily was established as not inferior to ABC + 3TC administered twice daily based on the proportion of nonvirologic failures (confirmed HIV-1 RNA level > or =1265 copies/mL; 90% confidence interval: -3.4 to 6.4; (intent to treat [ITT]: missing [M] = failure [F]). Proportions with an HIV-1 RNA level <50 copies/mL were 81% of those taking EPZ once daily and 82% of those taking ABC + 3TC twice daily at week 48 (ITT: M = F). Virologic failure was rare (2 patients taking the once-daily regimen, 4 patients taking the twice-daily regimen). There was a low incidence of grade 2 through 4 adverse events (AEs) and no drug-related serious AEs or hypersensitivity reactions. CONCLUSIONS: EPZ administered once daily was established as not inferior to ABC + 3TC administered twice daily in a regimen containing an NNRTI or a PI over 48 weeks. A dual-nucleoside backbone of ABC and 3TC administered once or twice daily is effective, durable, and well tolerated.