Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection.

Daily oral antiretroviral therapy regimens produce limited drug exposure in tissues where residual HIV persists and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir, tenofovir (TFV), and lamivudine (3TC). In 4 macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node mononuclear cells (LNMCs), and peripheral blood mononuclear cells (PBMCs) were analyzed by liquid chromatography-tandem mass spectrometry. Plasma and PBMC levels of the active drugs (LPV, TFV, and 3TC) were sustained for 5 weeks; PBMC exposures to LPV, ritonavir, and 3TC were 12-, 16-, 42-fold higher than those in plasma. Apparent T1/2z of LPV, TFV, and 3TC were 219.1, 63.1, and 136.3 h in plasma; 1045.7, 105.9, and 127.7 h in PBMCs. At day 8, LPV, TFV, and 3TC levels in LNMCs were 4.1-, 5.0-, and 1.9-fold higher than in those in PBMCs and much higher than in plasma. Therefore, 1 dose of a 4-drug nanosuspension exhibited persistent drug levels in LNMCs, PBMCs, and plasma for 5 weeks. With interspecies scaling and dose adjustment, this 4-in-1 HIV drug-combination could be a long-acting treatment with the potential to target residual virus in tissues and improve patient adherence.

HIV in central nervous system and behavioral development: an HIV-2287 macaque model of AIDS.

OBJECTIVE: To determine which route of inoculation produced consistent and frequent HIV infection in the central nervous system (CNS) and alterations in cognitive and motor development in infant macaques. METHODS: Infant macaques (Macaca nemestrina) were inoculated with the highly pathogenic strain HIV-2287 intravenously (n = 3) or intrathecally (n = 3). Uninfected infants were evaluated as controls. Disease progression was evaluated by virological assessment of blood and cerebral spinal fluid (CSF), CD4 T cell count in blood, and quinolinic acid levels in CSF (a surrogate marker of neuronal cell damage). The effect of HIV infection on cognitive and motor development in infants was monitored during the 6-month study. RESULTS: Either route of HIV-2287 inoculation produced detectable viral RNA in CSF and productive infection in blood. Detection of virus in CSF paralleled a rise in quinolinic acid levels. All HIV-infected infants experienced a severe and rapid decline in CD4 T cell counts by 10 weeks after viral infection. HIV-infected infants, particularly those infected by the intravenous route, exhibited delays in reaching cognitive and motor milestones, which paralleled neuropathological changes. CONCLUSIONS: The HIV-2287 infant model produced a high incidence of viral infection in the CNS regardless of the route of inoculation. Significant alteration in neurobehavioral development was observed in HIV-infected infants, and this measure was significantly impaired particularly in infants infected by the intravenous route. These data, coupled with the ability to detect viral RNA and changes in quinolinic acid levels in CSF, may allow quantitative evaluation of drug and immune candidates for treating neurological effects of AIDS.