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1.
N Engl J Med ; 375(21): 2037-2050, 2016 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-27959728

RESUMO

BACKGROUND: The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). METHODS: We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. RESULTS: A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 µg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus. CONCLUSIONS: VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV/isolamento & purificação , Viremia/prevenção & controle , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Amplamente Neutralizantes , Feminino , HIV/genética , Anticorpos Anti-HIV , Infecções por HIV/virologia , Estudo Historicamente Controlado , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , RNA Viral/sangue , Carga Viral
2.
J Infect Dis ; 215(11): 1725-1733, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28431010

RESUMO

Background: Reversing immune exhaustion with an anti-PD-L1 antibody may improve human immunodeficiency virus type 1 (HIV-1)-specific immunity and increase clearance of HIV-1-expressing cells. Methods: We conducted a phase I, randomized, double-blind, placebo-controlled, dose-escalating study of BMS-936559, including HIV-1-infected adults aged >18 to <70 years on suppressive antiretroviral therapy with CD4+ counts >350 cells/µL and detectable plasma HIV-1 RNA by single-copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any grade 3 or greater or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cell responses from baseline to day 28 after infusion. Results: Eight men enrolled: 6 received 0.3 mg/kg of BMS-936559, and 2 received placebo infusions. There were no BMS-936559-related grade 3 or greater AEs. In 1 participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days after BMS-936559 infusion; it resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing interferon γ increased from baseline (0.09%) through day 28 (0.20%; P = .14), driven by substantial increases in 2 participants who received BMS-936559. Conclusions: In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1-infected persons, single low-dose BMS-936559 infusions appeared to enhance HIV-1-specific immunity in a subset of participants. Clinical Trials Registration: NCT02028403.


Assuntos
Antirretrovirais/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Infecções por HIV/tratamento farmacológico , Adulto , Linfócitos T CD8-Positivos , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade
3.
J Clin Pharmacol ; 61(12): 1555-1566, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34169526

RESUMO

Ruxolitinib is a US Food and Drug Administration-approved orally administered Janus kinase (1/2) inhibitor that reduces cytokine-induced inflammation. As part of a randomized, phase 2, open-label trial, ruxolitinib (10 mg twice daily) was administered to HIV-positive, virologically suppressed individuals (33 men, 7 women) on antiretroviral therapy (ART) for 5 weeks. Herein, we report the population PK subsequently determined from this study. Plasma concentrations of ruxolitinib (294 samples) and antiretroviral agents were measured at week 1 (N = 39 participants) and week 4 or 5 (N = 37). Ruxolitinib PK was adequately described with a 2-compartment model with first-order absorption and elimination with distribution volumes normalized to mean body weight (91.5 kg) and a separate typical clearance for participants administered efavirenz (a known cytochrome P450 3A4 inducer). Participants administered an ART regimen with efavirenz had an elevated typical apparent oral clearance versus the integrase inhibitor regimen group (22.5 vs 12.9 L/hr; N = 14 vs 25). Post hoc predicted apparent oral clearance was likewise more variable and higher (P < .0001) in those administered efavirenz. There was  an ≈25% variation in ruxolitinib plasma exposures between week 1 and week 4/5. ART plasma concentrations resembled those from PK studies without ruxolitinib. Therefore, integrase inhibitor-based ART regimens may be preferred over efavirenz-based regimens when ruxolitinib is administered to HIV-positive individuals.


Assuntos
Alcinos/farmacologia , Antirretrovirais/uso terapêutico , Benzoxazinas/farmacologia , Ciclopropanos/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Infecções por HIV/tratamento farmacológico , Nitrilas/farmacocinética , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Adulto , Antirretrovirais/farmacocinética , Peso Corporal , Interações Medicamentosas , Feminino , Humanos , Janus Quinases/antagonistas & inibidores , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem
4.
J Clin Invest ; 130(6): 2845-2858, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32017709

RESUMO

Plasmacytoid dendritic cells (pDCs) are robust producers of IFNα and one of the first immune cells to respond to SIV infection. To elucidate responses to early HIV-1 replication, we studied blood pDCs in 29 HIV-infected participants who initiated antiretroviral therapy during acute infection and underwent analytic treatment interruption (ATI). We observed an increased frequency of partially activated pDCs in the blood before detection of HIV RNA. Concurrent with peak pDC frequency, we detected a transient decline in the ability of pDCs to produce IFNα in vitro, which correlated with decreased phosphorylation of IFN regulatory factory 7 (IRF7) and NF-κB. The levels of phosphorylated IRF7 and NF-κB inversely correlated with plasma IFNα2 levels, implying that pDCs were refractory to in vitro stimulation after IFNα production in vivo. After ATI, decreased expression of IFN genes in pDCs inversely correlated with the time to viral detection, suggesting that pDC IFN loss is part of an effective early immune response. These data from a limited cohort provide a critical first step in understanding the earliest immune response to HIV-1 and suggest that changes in blood pDC frequency and function can be used as an indicator of viral replication before detectable plasma viremia.


Assuntos
Células Dendríticas/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Viremia/imunologia , Replicação Viral/imunologia , Adulto , Células Dendríticas/patologia , Feminino , Infecções por HIV/patologia , Infecções por HIV/terapia , Humanos , Fator Regulador 7 de Interferon/imunologia , Interferon-alfa/imunologia , Masculino , NF-kappa B/imunologia , Viremia/patologia , Viremia/terapia
5.
J Virus Erad ; 5(1): 50-59, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30800428

RESUMO

The National Institute of Allergy and Infectious Diseases (NIAID) organised the Strategies for an HIV Cure 2018 meeting focused on research to develop innovative strategies for eradicating or achieving long-term remission of HIV infection. The purpose was to bring together researchers studying HIV persistence and cure strategies, including the six National Institutes of Health (NIH)-funded Martin Delaney Collaboratories for HIV Cure Research (MDCs), as well as industry and community partners, to share scientific results and stimulate active discussion among all stakeholders about the merits of various approaches under investigation. These discussions were intended to stimulate new collaborations and ideas for future research. The meeting covered a comprehensive range of topics spanning basic and translational research, drug discovery and development, and clinical research. Aside from the oral presentations described here, the meeting also included 130 poster presentations. Each of the three days of presentations is available for viewing via the NIH VideoCast website at: https://videocast.nih.gov/PastEvents.asp.

6.
J Clin Invest ; 128(7): 3102-3115, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29911997

RESUMO

BACKGROUND: The effect of a brief analytical treatment interruption (ATI) on the HIV-1 latent reservoir of individuals who initiate antiretroviral therapy (ART) during chronic infection is unknown. METHODS: We evaluated the impact of transient viremia on the latent reservoir in participants who underwent an ATI and at least 6 months of subsequent viral suppression in a clinical trial testing the effect of passive infusion of the broadly neutralizing Ab VRC01 during ATI. RESULTS: Measures of total HIV-1 DNA, cell-associated RNA, and infectious units per million cells (IUPM) (measured by quantitative viral outgrowth assay [QVOA]) were not statistically different before or after ATI. Phylogenetic analyses of HIV-1 env sequences from QVOA and proviral DNA demonstrated little change in the composition of the virus populations comprising the pre- and post-ATI reservoir. Expanded clones were common in both QVOA and proviral DNA sequences. The frequency of clonal populations differed significantly between QVOA viruses, proviral DNA sequences, and the viruses that reactivated in vivo. CONCLUSIONS: The results indicate that transient viremia from ATI does not substantially alter measures of the latent reservoir, that clonal expansion is prevalent within the latent reservoir, and that characterization of latent viruses that can reactivate in vivo remains challenging. TRIAL REGISTRATION: ClinicalTrials.gov NCT02463227FUNDING. Funding was provided by the NIH.


Assuntos
Antirretrovirais/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1 , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Amplamente Neutralizantes , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , DNA Viral/sangue , DNA Viral/genética , Esquema de Medicação , Genes env , Variação Genética/efeitos dos fármacos , Anticorpos Anti-HIV , Proteína gp160 do Envelope de HIV/genética , HIV-1/classificação , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Provírus/classificação , Provírus/efeitos dos fármacos , Provírus/genética , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Viremia/virologia , Latência Viral/efeitos dos fármacos , Latência Viral/genética
7.
Drugs ; 75(13): 1447-59, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26224205

RESUMO

Despite effective antiretroviral therapy (ART) and undetectable HIV RNA in the plasma, latent replication-competent HIV persists indefinitely in long-lived cells. Cessation of ART results in rebound of HIV from these persistent reservoirs. While this was thought to be an insurmountable obstacle to viral eradication, recent cases suggest otherwise. To date one patient has been "cured" of HIV and several others have been able to interrupt ART without viral rebound for prolonged periods. These events have sparked renewed interest in developing strategies that will allow eradication of HIV in infected individuals. We review the current knowledge of HIV latency and the viral reservoir, describe the potential utility of emerging cancer therapeutics in HIV cure research with an emphasis on pathways implicated in reservoir persistence, and outline opportunities and challenges in the context of the current clinical trial and regulatory environment.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Antineoplásicos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , HIV/efeitos dos fármacos , HIV/isolamento & purificação , Infecções por HIV/virologia , Humanos , Neoplasias/tratamento farmacológico
8.
Nutrition ; 18(6): 484-9, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12044821

RESUMO

OBJECTIVE: We tested the hypothesis that the gastrointestinal tolerance of a new infant formula equals or exceeds the tolerance of other milk-based infant formulas and compared the tolerance of this new formula with that of human milk. METHODS: This prospective, phase IV, open-label study was conducted in 17 countries. Healthy, full-term infants, 28 to 98 d old, were enrolled on their current feeding (no treatment assigned). Feeding regimens included human milk (HM), a new infant formula (NF; Similac Advance), other infant formula (OF), HM + NF, and HM + OF. Data for stool frequency, stool consistency, and gastrointestinal symptoms were collected in study diaries for 2 wk. RESULTS: Gastrointestinal tolerance was evaluated in 6999 infants: 979 (14.0%) received HM, 1695 (24.2%) received HM + NF, 635 (9.1%) received HM + OF, 2677 (38.2%) received NF, and 1013 (14.5%) received OF. Infants fed HM had softer and more frequent stools than did those who received NF, HM + NF, or OF (P < 0.001). Infants fed NF had softer and more frequent stools than did those fed OF (P < 0.001), including those fed Enfalac or S-26 (P < 0.001). Regurgitation (P < 0.001) and colic (P = 0.006) were more frequent with OF than with NF. All feeding regimens were well tolerated and only 3.5% of subjects experienced adverse events. CONCLUSIONS: This global study demonstrated that stools of infants fed NF are softer and more frequent than stools from infants fed OF and are closer to those of breast-fed infants. Infants consuming NF also experienced less regurgitation and colic than did infants in other feeding groups.


Assuntos
Sistema Digestório/efeitos dos fármacos , Alimentos Infantis/efeitos adversos , Animais , Cólica/epidemiologia , Cólica/etiologia , Constipação Intestinal/epidemiologia , Constipação Intestinal/etiologia , Fezes/química , Feminino , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/etiologia , Humanos , Lactente , Alimentos Infantis/análise , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Cooperação Internacional , Masculino , Leite/efeitos adversos , Leite Humano/metabolismo , Estudos Prospectivos , Segurança
9.
Nutrition ; 19(1): 16-20, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12507633

RESUMO

OBJECTIVE: The objective was to measure the total potentially available nucleosides (TPAN) in breast milk from Asian women. METHODS: One hundred sixty milk samples were collected from 135 healthy, lactating women in Hong Kong, the Philippines, and Singapore at four stages of lactation: colostrum (1 to 3 days postpartum), transitional (7 to 10 days postpartum), early mature (28 to 35 days postpartum), and late mature (90 to 100 days postpartum). Samples were pooled by site and stage of lactation before analysis. RESULTS: The mean TPAN concentration was 203 microM/L (69.4 mg/L corrected for recovery). Average TPAN concentrations were 171.9 microM/L in colostrum, 208.1 microM/L in transitional milk, 221.6 microM/L in early mature milk, and 210.6 microM/L in late mature milk, with no notable differences between countries. The major sources of nucleosides were RNA (43.3% of TPAN) and free nucleotides (39.9% of TPAN). The average percentages of cytidine, uridine, guanosine, and adenosine monophosphates were 44.5%, 23.1%, 16.5%, and 16.1% of TPAN, respectively. The sources of nucleosides and percentages of nucleotide bases were similar for all stages of lactation. Over 91% of the TPAN was present in the non-cellular component except in colostrum. CONCLUSIONS: The average TPAN level in Asian women is similar to that in European and American women, and free nucleotides in human milk represent less than half of the TPAN.


Assuntos
Colostro/química , Lactação , Leite Humano/química , Nucleosídeos/análise , Adulto , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Hong Kong , Humanos , Filipinas , Sensibilidade e Especificidade , Singapura
10.
Asia Pac J Clin Nutr ; 11(2): 151-6, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12074183

RESUMO

The objective of this study was to test whether the gastrointestinal tolerance of a new infant formula equalled or exceeded the tolerance of other milk-based infant formulas, and to compare the tolerance of the new formula to that of human milk. This prospective, observational, multicenter, open-label study was conducted in Taiwan. Healthy, full-term infants aged 28-98 days were enrolled on their current feeding regimen (no treatment assigned). Feeding regimens included human milk (HM), a new infant formula (NF, Similac Advance), other marketed infant formulas (OF, mainly Enfalac or S-26, HM + NF and HM + OF. Data for stool frequency, stool consistency and gastrointestinal intolerance symptoms were recorded in study diaries by parents for a period of two weeks. Gastrointestinal tolerance was evaluated in 967 infants, of whom 481 (49.7%) received NF, 312 (32.2%) received OF, 101 (10.4%) received HM + NF, 41 (4.2%) received HM + OF and 32 (3.3%) received HM. Infants fed HM only had softer and more frequent stools than those who received NF only or OF only (P < 0.001). Infants fed NF only had softer stools than those fed OF only (P < 0.001), including those fed either Enfalac or S-26 (P < 0.001). There were no significant differences between feeding groups for the incidence of general intolerance, spit-up or flatulence. All feeding regimens were well tolerated. We thereby concluded that NF is well tolerated in healthy infants and results in stool consistencies that more closely resemble those of infants fed human milk than those of infants fed other formulas.


Assuntos
Sistema Digestório/efeitos dos fármacos , Gastroenteropatias/etiologia , Alimentos Infantis/efeitos adversos , Leite Humano , Análise de Variância , Defecação/efeitos dos fármacos , Fezes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Valores de Referência , Taiwan
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