Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIVReport as inadecuate

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Journal of Translational Medicine

, 14:148

Clinical translation


BackgroundMany HIV infected individuals with suppressed viral loads experience chronic immune activation frequently developing neurological impairment designated as HIV associated neurocognitive disorder HAND. Adjunctive therapies may reduce HIV associated inflammation and therefore decrease the occurrence of HAND.

MethodsWe have conducted in vitro, animal and clinical studies of the neurokinin 1 receptor NK1R antagonist aprepitant in HIV-SIV infection.

ResultsAprepitant inhibits HIV infection of human macrophages ex vivo with an ED50 ~ 5 µM. When administered at 125 mg once daily for 12 months to SIV-infected rhesus macaques, aprepitant reduced viral load by approximately tenfold and produced anti-anxiolytic effects. The anti-viral and anti-anxiolytic effects occur at approximately the third month of dosing; and the effects are sustained throughout the duration of drug administration. Protein binding experiments in culture media and animal and human plasma indicate that the free fraction of aprepitant is lower than previously reported supporting usage of higher doses in vivo. The analysis of blood samples from HIV positive individuals treated for 2 weeks with aprepitant at doses up to 375 mg demonstrated reduced levels of pro-inflammatory cytokines including G-CSF, IL-6, IL-8 and TNFα. Decreased pro-inflammatory cytokines may reduce HIV comorbidities associated with chronic inflammation.

ConclusionsOur results provide evidence for a unique combination of antiretroviral, anti-inflammatory and behavioral modulation properties of aprepitant in vitro and in vivo. These results provide robust support for a clinical exposure target above that recommended for chemotherapy-induced nausea and vomiting. Doses up to 375 mg once daily in HIV-infected patients still elicit sub-therapeutic exposure of aprepitant though effective plasma concentrations can be achievable by proper dose modulation.

KeywordsHIV SIV HIV associated neurocognitive disorder Substance P Neurokinin 1 receptor Aprepitant Inflammation AbbreviationsHANDHIV associated neurocognitive disorder

NK1Rneurokinin 1 receptor

HIVhuman immunodeficiency virus

SIVsimian immunodeficiency virus

G-CSFgranulocyte-colony stimulating factor

IL-6interleukin 6

IL-8interleukin 8

TNFαtumor necrosis factor alpha

MIP-1αmacrophage inflammatory protein 1-alpha

cARTcombined antiretroviral therapy

AIDSacquired immune deficiency syndrome

CINVchemotherapy induced nausea and vomiting

SPsubstance P

SCIDstructured diagnostic psychiatric assessments

PBMCperipheral blood mononuclear cell

MDMmonocyte derived macrophages


FBSfetal bovine serum

PD-1programmed death

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