Combination therapy with anti-HIV-1 antibodies maintains viral suppression.

Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg kg-1 of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well-tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.

Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117.

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.

Randomized, double-blind, controlled study of glycyl-glutamine-dipeptide in the parenteral nutrition of patients with acute leukemia undergoing intensive chemotherapy.

OBJECTIVE: Glutamine has stimulatory effects on lymphocytes and mucosa cells in vitro and, when given with parenteral nutrition, has been shown to improve the clinical course of patients after bone marrow transplantation and in the critically ill. This study investigated the clinical and immunologic effects of parenteral glycyl-glutamine supplementation in patients with acute leukemia receiving intensive conventional chemotherapy without bone marrow transplantation. METHODS: A randomized, double-blind, controlled study compared a standard glutamine-free parenteral nutrition with a glycyl-glutamine-supplemented parenteral nutrition (Glamin, Baxter, Erlangen, Germany) containing 20 g of glutamine in adult patients with acute myeloid leukemia undergoing myelosuppressive chemotherapy. Clinical end points included the duration of neutropenia and the incidence and duration of neutropenic fever. To analyze the effects of glutamine on immunocompetent cells, CD4+ and CD8+ T cells and HLA-DR expression on monocytes were assessed by flow cytometry throughout the treatment course. RESULTS: Fifty-four adult patients entered the study and were randomized. In 45 of 127 chemotherapy cycles, parenteral nutrition was given, and 40 cycles (20 with and 20 without glutamine) were evaluated for comparison. The median durations of neutropenia were 18 d (range, 9-29 d) in the glutamine group and 22.5 d (range, 13-48 d) in the control group (P = 0.052), whereas the median durations of neutropenic fever were 5.5 d (range, 0-13 d) and 5 d (range, 0-31 d), respectively (P = 0.74). Using Kaplan-Meier analysis and controlling for the type of chemotherapy, we found a significantly faster neutrophil recovery in patients receiving glutamine than in the control group (P = 0.040) in patients receiving a high-dose cytarabine regimen. There was no significant difference in the recovery of CD4+ or CD8+ lymphocytes or monocyte activation between groups. CONCLUSION: In patients with acute myeloid leukemia requiring parenteral nutrition, glycyl-glutamine supplementation could hasten neutrophil recovery after intensive myelosuppressive chemotherapy. However, no impact of glutamine on neutropenic fever or other criteria of immunologic recovery was detected.

Fibrosis y cirrosis en el conejo por acción del dietilestilbestrol y su inhibición por la progesterona / Fibrosis and cirrhosis in the rabbit induced by diethylestilbestrol and its inhibition with progesterone

El dietilestilbestrol administrado por boca en forma prolongada (más de tres meses) produce en conejos una intensa fibrosis o cirrosis hepática. Se investigó el efecto de la progesterona inyectada en forma intramuscular día por medio (33 mg) respecto a esta fibrosis hormonal. Se estudiaron cuatro lotes de conejos. En el primero (lote A) compuesto por once conejos, se administró el estrógeno, se realizaron biopsias quirúrgicas seriadas y se comprobó la existencia de fibrosis después de los tres meses de iniciado el estrógeno. Al suspender el dietilestilbestrol la fibrosis desapareció paulatinamente hasta que no era histológicamente comprobable a los ocho meses de la suspensión. En el segundo (lote B) se administró conjuntamente el dietilestilbestrol y la progesterona en nueve conejos. El estudio histológico demostró que la progesterona impedía totalmente o disminuía la formación del tejido conectivo. El tercero (lote C) estaba compuesto por trece conejos, ocho recibieron dietilestilbestrol durante un período de cuatro a doce meses y sirvieron de testigos a cinco conejos que recibieron dietilestilbestrol durante seis meses, y a éstos sin suspender el estrógeno, se les añadió progesterona. Los conejos se sacrificaron a los cuatro meses y a los nueve meses de recibir la progesterona. Se comprobó que la fibrosis era mucho menor que en los conejos que no habían recibido progesterona. Se hicieron tambíen mediciones de enzimas, bilirrubina, etc., a todos los lotes sin que se comprobaran alteraciones con respecto a los valores normales, y se realizó también el estudio histológico de conejos que habían recibido solamente progesterona en forma prolongada sin encontrar anormalidades. Se concluye que en la fibrosis y cirrosis producida en conejos por la administración prolongada de dietilestilbestrol, la progesterona administrada simultáneamente impide totalmente o disminuye al mínimo el aumento del tejido conectivo. Administrada una vez producida la fibrosis y sin eliminar el estrógeno, la progesterona disminuye el aumento del tejido conectivo provocado por el dietilestilbestrol