Phase II study to evaluate the efficacy and safety of baricitinib for reduction of HIV in the central nervous system
II 期研究评估 baricitinib 减少中枢神经系统 HIV 的有效性和安全性
基本信息
- 批准号:10681470
- 负责人:
- 金额:$ 63.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-10 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AIDS clinical trial groupAntibodiesAuthorization documentationBehavioralBiological AssayBiological AvailabilityBloodBrainCOVID-19CXCL10 geneCellsCentral Nervous SystemCerebrospinal FluidClinicClinicalDNADataDoseDrug KineticsEmergency SituationEncephalitisFDA approvedFutureGeneticGoalsHIVHIV AntibodiesHIV Envelope Protein gp120HIV InfectionsIL7 geneImmunologic MarkersIn VitroIndividualInfectionInterleukin-15InterventionJanus kinaseLightLinkLongevityMacaca mulattaMagnetic Resonance ImagingMental DepressionMicrotubule-Associated Protein 2ModelingMorbidity - disease rateMyelofibrosisNeopterinNeurocognitive DeficitNeuronsNeuropsychologyOpportunistic InfectionsOralParticipantPerformancePeripheralPersonsPharmaceutical PreparationsPhasePlacebosPolycythemia VeraPropertyPublishingRNARandomizedRegimenRenal clearance functionReportingResearchRetroviridae InfectionsRheumatoid ArthritisRiskSafetySiteSourceSpectrum AnalysisTestingTherapeuticVirusVirus DiseasesWorkantiretroviral therapyauthoritybrain parenchymabrain tissuecytokinedepressive symptomsefficacy evaluationimmune activationimprovedin vivoinflammatory markerinhibitorinhibitor therapyinnovationmembermortalitymouse modelneurofilamentneuroprotectionnovelphase 2 studyphase 3 studyphenotypic biomarkerpre-clinicalpreferencerandomized placebo controlled studyside effectsocial stigmasymposium
项目摘要
Project Summary/Abstract
Although HIV infection is controllable with antiretroviral therapy (ART), HIV cure continues to be
extremely elusive. Cure of HIV is desperately needed for many reasons. People with HIV (PWH) have persistent
increases in morbidity and mortality despite ART, and while newer ART agents have become better tolerated,
they are still associated with multiple side effects. Having to attend HIV clinics and take ART over the long term
still carries significant stigma for PWH. Additionally, many PWH have a preference for cure rather than a lifetime
of ART, and some would take significant risks to achieve a cure. For all of these reasons, finding a cure for HIV
is one of the ultimate goals of the field.
There is a large and growing body of evidence that the central nervous system (CNS) is an HIV reservoir
site that represents another barrier to HIV eradication. HIV DNA is commonly found in brain tissue from PWH on
suppressive ART, and there are multiple published reports of CNS virologic escape. Multiple studies, including
from our group, have demonstrated that HIV RNA can be detected at very low levels in CSF during suppressive
ART and that anti-HIV antibodies are also present in the CSF among individuals on ART. New members of our
group recently presented findings with an innovative assay (Double-R) to reliably quantitate HIV RNA and DNA
from CSF.
Our group has performed extensive pre-clinical and clinical work on the Janus Kinase (Jak 1/2) inhibitor
drug class to target HIV. This includes work on baricitinib, an FDA approved orally bioavailable Jak 1/2 inhibitor
for rheumatoid arthritis. We have demonstrated that baricitinb blocks HIV replication, HIV-induced activation and
infection in key CNS cells, and reservoir reseeding. In vivo, we have shown in our murine model that baricitinib
decreases CNS HIV and reverses behavioral abnormalities conferred by HIV. We have also demonstrated that
baricitinib achieves therapeutic CNS concentrations in the rhesus macaque model. We now propose to study
baricitinib as a therapy to decrease the HIV CNS reservoir in a study of PWH with durable virologic suppression
on ART. This will be a phase IIa randomized placebo controlled study. Our primary hypothesis is that individuals
randomized to baricitinib will be more likely to achieve a decrease in CSF cell associated HIV RNA and DNA by
Double-R assay. We also hypothesize that baricitinib treatment will be associated with a significant decrease in
other markers of HIV CNS persistence, including HIV-specific CSF antibodies, CSF cell associated DNA
including by Integrated Proviral DNA (IPDA), CSF RNA by single copy assay, CSF HIV Tat levels, and markers
of inflammation that have been linked to CNS HIV persistence, as well as magnetic resonance imaging and
spectroscopy markers. Additionally, we hypothesize that baricitinib treatment will be safe for the CNS as defined
by neuropsychological performance, depression symptoms, and neuronal damage. We are confident that this
study will provide a strong basis for baricitinib to be included in regimens that target eradication of HIV.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christina Gavegnano其他文献
Christina Gavegnano的其他文献
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{{ truncateString('Christina Gavegnano', 18)}}的其他基金
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阐明肠道储存库和炎症在艾滋病毒感染者心血管疾病中的作用
- 批准号:
10548049 - 财政年份:2022
- 资助金额:
$ 63.84万 - 项目类别:
Elucidating the role of the gut reservoir and inflammation in driving cardiovascular disease among persons living with HIV
阐明肠道储存库和炎症在艾滋病毒感染者心血管疾病中的作用
- 批准号:
10670393 - 财政年份:2022
- 资助金额:
$ 63.84万 - 项目类别:
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