It is estimated that about 2.1 million children worldwide are living with HIV. Due to their physio-pharmacological distinction, pediatric drug treatments require age appropriate dosage form. However, the development of therapeutics aimed at suppressing HIV in children and adolescents has been limited. In contrast to a larger selection of oral combination antiretroviral therapies (cART) available for adults, the options for children are somewhat limited. Also, data indicates that only about 30% of adolescents experience durable viral suppression. Even in cases with plasma viral suppression, residual virus can be isolated from tissues, particularly lymph nodes. Therefore, we have developed a drug combination nanoparticle (DcNP) containing three drugs with well-established antiviral potency and safety in pediatrics, targeting three different stages in the viral replication. This DcNP is composed of a protease inhibitor lopinavir (LPV), nonnucleoside reverse transcriptase inhibitor efavirenz (EFZ), and nucleoside inhibitor tenofovir (TFV). The objective of this study was to characterize targeted and long-acting effects of our validated 3-drug single DcNP formulation in HIV host cells and plasma in non-human primates for two weeks.
Macaques were given a single dose of the DcNP subcutaneously. The drug concentrations in plasma, peripheral blood, and lymph mononuclear cells were analyzed for two weeks. The pharmacokinetic parameters and cell-to-plasma relationship of the three drugs were determined.
The formulation was well-tolerated in primate and no local reactions were noted. We found that protease inhibitor (LPV) and reverse transcriptase inhibitor (EFV, TFV) levels persist in plasma for the two week duration of the study. Intracellular levels for all three drugs also persist for two weeks and exhibit higher levels, especially for EFV and LPV, than those found in plasma. All three drugs also exhibit lymph node drug concentrations higher than plasma (table 1).
Collectively, this 3-in-1 DcNP formulation provided long-acting plasma drug concentration and enhanced HIV host-cell localization in cells in blood and also lymph nodes. This anti-HIV DcNP formulation should be considered for development intended for pediatrics. With long-acting profile and higher penetration/persistence in cells, it may enhance therapeutic efficacy of these well-studied HIV drugs due to co-localization of a combination of three drugs.