RESUMEN
HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/terapia , VIH-1/inmunología , Carga Viral/inmunología , Viremia/terapia , Adulto , Secuencia de Aminoácidos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/efectos adversos , Anticuerpos Neutralizantes/farmacología , Anticuerpos Neutralizantes/uso terapéutico , Sitios de Unión , Anticuerpos ampliamente neutralizantes , Antígenos CD4/metabolismo , Estudios de Casos y Controles , Evolución Molecular , Femenino , Anticuerpos Anti-VIH/administración & dosificación , Anticuerpos Anti-VIH/efectos adversos , Anticuerpos Anti-VIH/farmacología , Anticuerpos Anti-VIH/uso terapéutico , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/química , VIH-1/efectos de los fármacos , Humanos , Inmunización Pasiva/métodos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Factores de Tiempo , Carga Viral/efectos de los fármacos , Viremia/inmunología , Viremia/virología , Adulto JovenRESUMEN
BACKGROUND: Adherence is critical to achieve the benefits of antiretroviral therapy. A smart-pill bottle service that transmits real-time adherence data via cellular networks to a central service and prompts nonadherent patients with phone or text messages may improve adherence. METHODS: Adults with HIV taking a tenofovir-containing regimen with suboptimal adherence were randomized to adherence counseling ± a smart-pill bottle service for 12 weeks. Tenofovir diphosphate (TFV-DP) levels by dried blood spot, HIV RNA levels, CD4 cell counts, and self-reported adherence were collected. RESULTS: Sixty-three participants (22% women; 48% black, 25% Latino) were randomized: 30 to the smart-pill bottle (2 of whom were lost to follow-up before the baseline visit), and 33 to control arms. At baseline, 49% of participants had HIV RNA ≤20 copies/mL and 61% reported 100% adherence with ART over 4 days. From baseline to week 12, median TFV-DP levels were +252 and -41 fmol/punch in the bottle and control arms, respectively (P = 0.10). Exploratory exclusion of 3 participants with known or suspected drug-drug interactions found median TFV-DP levels of +278 and -38 fmol/punch, respectively (P = 0.04). There were no differences in study discontinuations, HIV RNA suppression, CD4 cell counts, or self-reported adherence at week 12. CONCLUSIONS: In a diverse group of participants with suboptimal adherence to ART, the smart-pill bottle service was associated with higher TFV-DP levels.